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346 results on '"Churchill G"'

1. A master protocol to investigate a novel therapy acetyl-l-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia

Author

Fields, T., Patterson, M., Bremova-Ertl, T., Belcher, G., Billington, I., Churchill, G. C., Davis, W., Evans, W., Flint, S., Galione, A., Granzer, U., Greenfield, J., Karl, R., Kay, R., Lewi, D., Mathieson, T., Meyer, T., Pangonis, D., Platt, F. M., Tsang, L., Verburg, C., Factor, M., and Strupp, M.

Published
2021
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5. N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study

Author

Fields, T, Bremova, T M, Billington, I, Churchill, G C, Evans, W, Fields, C, Galione, A, Kay, R, Mathieson, T, Martakis, K, Patterson, M, Platt, F, Factor, M, and Strupp, M

Subjects
Medicine (miscellaneous), Pharmacology (medical), 610 Medicine & health
Abstract

Background Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code “IB1001-301”) for the chronic treatment of symptoms in adult and pediatric patients with NPC. Methods This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments. Discussion Pre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders. Trial registrations The trial (IB1001-301) has been registered at www.clinicaltrials.gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021–005356-10). Registered on 20 December 2021.

Published
2023

6. Genetic mapping of microbial and host traits reveals production of immunomodulatory lipids by Akkermansia muciniphila in the murine gut

Author

Zhang, Q., primary, Linke, V., additional, Overmyer, K. A., additional, Traeger, L. L., additional, Kasahara, K., additional, Miller, I. J., additional, Manson, D. E., additional, Polaske, T. J., additional, Kerby, R. L., additional, Kemis, J. H., additional, Trujillo, E. A., additional, Reddy, T. R., additional, Russell, J. D., additional, Schueler, K. L., additional, Stapleton, D. S., additional, Rabaglia, M. E., additional, Seldin, M., additional, Gatti, D. M., additional, Keele, G. R., additional, Pham, D. T., additional, Gerdt, J. P., additional, Vivas, E. I., additional, Lusis, A. J., additional, Keller, M. P., additional, Churchill, G. A., additional, Blackwell, H. E., additional, Broman, K. W., additional, Attie, A. D., additional, Coon, J. J., additional, and Rey, F. E., additional

Published
2023
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9. Fully integrated Si-rich silicon nitride wavelength converter based on Bragg scattering intermodal four-wave mixing

Author

Vitali, V., primary, Bucio, T. D., additional, Liu, H., additional, González, J. M. L., additional, Jurado-Romero, F., additional, Ortega-Moñux, A., additional, Churchill, G., additional, Gates, J. C., additional, Hillier, J., additional, Kalfagiannis, N., additional, Melati, D., additional, Schmid, J. H., additional, Cristiani, I., additional, Cheben, P., additional, Wangüuemert-Pérez, J. G., additional, Molina-Fernández, Í., additional, Gardes, F., additional, Lacava, C., additional, and Petropoulos, P., additional

Published
2023
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10. Iron-induced cytotoxicity mediated by endolysosomal TRPML1 channels is reverted by TFEB.

Author

Instituto de Salud Carlos III, European Commission, Agencia Estatal de Investigación (España), Junta de Andalucía, Consejo Superior de Investigaciones Científicas (España), Rutgers University, Fernández, Belén, Olmedo, Pablo, Gil, Fernando, Fdez, Elena, Naaldijk, Y., Rivero-Ríos, Pilar, Bracher, Franz, Grimm, Christian, Churchill, G. C., Hilfiker, Sabine, Instituto de Salud Carlos III, European Commission, Agencia Estatal de Investigación (España), Junta de Andalucía, Consejo Superior de Investigaciones Científicas (España), Rutgers University, Fernández, Belén, Olmedo, Pablo, Gil, Fernando, Fdez, Elena, Naaldijk, Y., Rivero-Ríos, Pilar, Bracher, Franz, Grimm, Christian, Churchill, G. C., and Hilfiker, Sabine

Abstract

Increased brain iron content has been consistently reported in sporadic Parkinson’s disease (PD) patients, and an increase in cytosolic free iron is known to cause oxidative stress and cell death. However, whether iron also accumulates in susceptible brain areas in humans or in mouse models of familial PD remains unknown. In addition, whilst the lysosome functions as a critical intracellular iron storage organelle, little is known about the mechanisms underlying lysosomal iron release and how this process is influenced by lysosome biogenesis and/or lysosomal exocytosis. Here, we report an increase in brain iron content also in PD patients due to the common G2019S-LRRK2 mutation as compared to healthy age-matched controls, whilst differences in iron content are not observed in G2019S-LRRK2 knockin as compared to control mice. Chemically triggering iron overload in cultured cells causes cytotoxicity via the endolysosomal release of iron which is mediated by TRPML1. TFEB expression reverts the iron overload-associated cytotoxicity by causing lysosomal exocytosis, which is dependent on a TRPML1-mediated increase in cytosolic calcium levels. Therefore, approaches aimed at increasing TFEB levels, or pharmacological TRPML1 activation in conjunction with iron chelation may prove beneficial against cell death associated with iron overload conditions such as those associated with PD.

Published
2022

14. Poster abstracts

Author

Ferrie, J., Shipley, M., Cappuccio, F., Brunner, E., Miller, M., Kumari, M., Marmot, M., Coenen, A., Castillo, J. L., Araya, F., Bustamante, G., Montecino, L., Torres, C., Oporto, S., Gronli, J., Fiske, E., Murison, R., Bjorvatn, B., Sorensen, E., Ursin, R., Portas, C. M., Rajaraman, S., Gribok, A., Wesensten, N., Balkin, T., Reifman, J., Dursunoglu, N., Ozkurt, S., Baser, S., Delen, O., Sarikaya, S., Sadler, P., Mitchell, P., Françon, D., Decobert, M., Herve, B., Richard, A., Griebel, G., Avenet, P., Scatton, B., Fur, G. L., Eckert, D., Jordan, A., Wellman, A., Smith, S., Malhotra, A., White, D., Bruck, D., Thomas, I., Kritikos, A., Oertel, W., Stiasny-Kolster, K., Garcia-Borreguero, D., Poewe, W., Hoegl, B., Kohnen, R., Schollmayer, E., Keffel, J., Trenkwalder, C., Valle, A., Roizenblatt, S., Fregni, F., Boggio, P., Tufik, S., Ward, K., Robertson, L., Palmer, L., Eastwood, P., Hillman, D., Lee, J., Mukherjee, S., de Padova, V., Barbato, G., Ficca, G., Zilli, I., Salzarulo, P., Veldi, M., Hion, T., Vasar, V., Kull, M., Nowak, L., Davis, J., Latzer, Y., Tzischinsky, O., Crowley, S., Carskadon, M., Anca-Herschkovitsch, M., Frey, D., Ortega, J., Wiseman, C., Farley, C., Wright, K., Campbell, A., Neill, A., Spiegel, K., Leproult, R., Tasali, E., Scherberg, N., van Cauter, E., Noradina, A. T., Karim, N. A., Norlinah, I., Raymond, A. A., Sahathevan, R., Hamidon, B., Werth, E., Poryazova, R., Khatami, R., Bassetti, C., Beran, R. G., Ainley, L., Holand, G., Duncan, J., Kinney, H., Davis, B., Hood, B., Frey, S., Schmidt, C., Hofstetter, M., Peigneux, P., Cajochen, C., Hu, W.-P., Li, J.-D., Zhang, C., Boehmer, L., Siegel, J., Zhou, Q.-Y., Sagawa, Y., Kondo, H., Takemura, T., Kanayama, H., Kaneko, Y., Sato, M., Kanbayashi, T., Hishikawa, Y., Shimizu, T., Viola, A., James, L., Schlangen, L., Dijk, D.-J., Andretic, R., Kim, Y.-C., Han, K.-A., Jones, F., Greenspan, R., Sanford, L., Yang, L., Tang, X., Dieter, K., Uta, E., Sven, H., Richard, M., Oyane, N., Pallesen, S., Holsten, F., Inoue, Y., Fujita, M., Emura, N., Kuroda, K., Uchimura, N., Johnston, A., Astbury, J., Kennedy, G., Hoedlmoser, K., Schabus, M., Pecherstorfer, T., Moser, S., Gruber, G., Anderer, P., Klimesch, W., Naidoo, N., Ferber, M., Pack, A., Neu, D., Mairesse, O., Hoffmann, G., Dris, A., Lambrecht, L., Linkowski, P., Verbanck, P., Le Bon, O., Matsuura, N., Yamao, M., Adachi, N., Aritomi, R., Komada, Y., Tanaka, H., Shirakawa, S., Kondoh, H., Takemura, F., Ohnuma, S., Suzuki, M., Uemura, S., Iskra-Golec, I., Smith, L., Thanh, D.-V., Boly, M., Phillips, C., Steven, L., Luxen, A., Maquet, M., Jay, S., Dawson, D., Lamond, N., Basner, M., Fomberstein, K., Dinges, D., Ogawa, K., Nittono, H., Yamazaki, K., Hori, T., Glamann, C., Hornung, O., Hansen, M.-L, Danker-Hopfe, H., Jung, C., Kecklund, G., Anund, A., Peters, B., Åkerstedt, T., Verster, J., Roehrs, T., Mets, M., de Senerpont Domis, L., Olivier, B., Volkerts, E., Knutson, K., Lauderdale, D., Rathouz, P., Christie, M., Chen, L., Bolortuya, Y., Lee, E., Mckenna, J., Mccarley, R., Strecker, R., Tamaki, M., Matsuoka, T., Aritake, S., Suzuki, H., Kuriyama, K., Ozaki, A., Abe, Y., Enomoto, M., Tagaya, H., Mishima, K., Matsuura, M., Uchiyama, M., Lima-Pacheco, E., Davis, K., Sabourin, C., Lortie-Lussier, M., de Koninck, J., van Der Werf, Y., van Der Helm, E., Schoonheim, M., van Someren, E., Tokley, M., Ball, M., Sato, T., Ghilardi, M. F., Moisello, C., Bove, M., Busi, M., Pelosin, E., Tononi, G., Eguchi, N., Sakata, M., Urade, Y., Doe, N., Yoshihara, K., Abe, K., Manabe, Y., Iwatsuki, K., Hayashi, T., Shoji, M., Kamiya, T., Gooley, J., Brainard, G., Rajaratnam, S., Kronauer, R., Czeisler, C., Lockley, S., Phillips, A., Robinson, P., Burgess, H., Revell, V., Eastman, C., Bihari, S., Ramakrishnan, N., Camerino, D., Conway, P. M., Costa, G., Vandewalle, G., Albouy, G., Sterpenich, V., Darsaud, A., Rauchs, G., Berken, P.-Y, Balteau, E., Maquet, P., Tendero, J. A., Domenech, M. P., Isern, F. S., Martínez, C., Roure, N., Sancho, E. E., Moreno, C. R., Silva, M., Marqueze, E. C., Waage, S., Bobko, N., Chernyuk, V., Yavorskiy, Y., Saxvig, I., Sørensen, E., de Mello, M. T., Esteves, A., Teixeira, C., Bittencourt, L. R., Silva, R., Pires, M. L., Mottram, V., Middelton, B., Arendt, J., Amaral, O., Rodrigues, M., Pereira, C., Tavares, I., Baba, K., Honma, S., Honma, K.-I., Yamanaka, Y., Hashimoto, S., Tanahashi, Y., Nishide, S.-Y, Honma, K.-I, Sletten, T., Middleton, B., Lederle, K., Skene, D., Roth, T., Walsh, J., Hogben, A., Ellis, J., Archer, S., von Schantz, M., Chen, N.-H., Wang, P.-C., Chen, C.-W., Lin, Y., Shih, T.-S., Armstrong, S., Redman, J., Stephan, E., David, M., Delanaud, S., Chardon, K., Libert, J.-P., Bach, V., Telliez, F., Reid, K., Jaksa, A., Eisengart, J., Kane, P., Naylor, E., Zee, P., Viola, A. U., de Valck, E., Hofmans, J., Theuns, P., Cluydts, R., Alexander, G., Karel, M., Christina, R., Sohn, I.-K., Cho, I. H., Kim, S. J., Yu, S.-H., Kim, H., Yoo, S. Y., Koh, S.-H., Cho, S.-J., Rotenberg, L., Silva-Costa, A., Griep, R. H., Amely, T., Kennedy, G. A., Pavlis, A., Thompson, B., Pierce, R., Howard, M., Briellmann, R., Venkateswaran, S., Blunden, S., Krawczyk, E., Blake, J., Gururajan, R., Kerr, D., Matuisi, T., Iwasaki, M., Yamasita, N., Iemura, A., Ohya, T., Yanagawa, T., Misa, R., Coleman, G., Conduit, R., Duce, B., Hukins, C., Nyandaiti, Y. W., Bamaki, S., Mohammed, A., Kwajarfa, S., Veeramachaneni, S. P., Murthy, A., Wilson, A., Maul, J., Hall, G., Stick, S., Moseley, L., Gradisar, M., Kurihara, T., Yamamoto, M., Yamamoto, S., Kuranari, M., Sparks, C. B., Bartle, A., Beckert, L., Latham-Smith, F. B., Hilton, J., Whitehead, B., Gulliver, T., Salvini, A., Grahame, S., Swift, M., Laybutt, N., Sharon, D., Mack, C., Hymell, B., Perrine, B., Ideshita, K., Taira, M., Matuo, A., Furutani, M., van Dongen, H., Mott, C., Huang, J.-K., Mollicone, D. J., Mckenzie, F., Dinges, David, Barnes, M., Rochford, P., Churchward, T., O’Donoghue, F., Penzel, T., Fietze, I., Canisius, S., Bekiaris, E., Terrill, P. I., Wilson, S., Suresh, S., Cooper, D., Suzuki, T., Ouchi, K., Moriya, A., Kameyama, K., Takahashi, M., Büttner, A., Rühle, K.-H., Wang, D., Wong, K., Dungan, II, G., Grunstein, R., Davidson, P., Jones, R., Gergely, V., Mashima, K., Miyazaki, S., Tanaka, T., Okawa, M., Yamada, N., Wyner, A., Raizen, D., Galante, R., Ng, A. K., Koh, T. S., Lim, L. L., Puvanendran, K., Peiris, M., Bones, P., Roebuck, T., Ho, S., Szollosi, I., Naughton, M., Williams, G., Parsley, C., Harris, M.-A., Thornton, A., Ruehland, W., Banks, S., Arroyo, S., Carroll, K., Pilmore, J., Stewart, C., Hamilton, G., van Acker, F., Cvetkovic, D., Holland, G., Cosic, I., Tolson, J., Worsnop, C., Cresswell, P., Hart, I., Bouarab, M., Delechelle, E., Drouot, X., Acebo, C., Singh, P., Lakey, T., Schachter, L., Rand, J., Collin, H., Snyder, E., Ma, J., Svetnick, V., Deacon, S., Dana, B., Konstanze, D., Uwe, M., Ingo, F., Thomas, P., Ivar, R., Mackiewicz, M., Shockley, K., Romer, M., Zimmerman, J., Baldwin, D., Jensen, S., Churchill, G., Paigen, B., Imeri, L., Ferrari, L., Bianchi, S., Dossena, S., Garofoli, A., Mangieri, M., Tagliavini, F., Forloni, G., Chiesa, R., Pedrazzoli, M., Pereira, D., Veauny, M., Bodenmann, S., Hohoff, C., Freitag, C., Deckert, J., Rétey, J., Landolt, H.-P., Strohl, K., Price, E., Yamauchi, M., Dostal, J., Feng, P., Han, F., Havekes, R., Novati, A., Hagewoud, R., Barf, P., van Der Borght, K., van Der Zee, E., Meerlo, P., Ruby, P., Caclin, A., Boulet, S., Delpuech, C., Morlet, D., Veasey, S., Aton, S., Jha, S., Coleman, T., Seibt, J., Frank, M., Lack, L., Churches, O., Feng, S. Y. S., Cassaglia, P., Yu, V. Y. H., Walker, A. M., Kohler, M., Kennedy, D., Martin, J., van Den Heuvel, C., Lushington, K., Herron, K., Khurana, C., Sterr, A., Olivadoti, M., Toth, L., Opp, M., Dang-Vu, T., Degueldre, C., Gais, S., Dang-Vu, T. T., Desseilles, M., Philips, C., Chijavadze, E., Babilodze, M., Chkhartishvili, E., Nachkebia, N., Mchedlidze, O., Dzadzamia, S., Griffiths, R., Walker, A., Horovitz, S., Fukunaga, M., Carr, W., Picchioni, D., de Zwart, J., van Gelderen, P., Braun, A., Duyn, J., Hanlon, E. H., Faraguna, U., Vyazovskiy, V., Cirelli, C., Ocampo-Garcés, A., Ibáñez, F., López, S., Vivaldi, E., Torrealba, F., Romanowski, C. P. N., Fenzl, T., Flachskamm, C., Deussing, J., Kimura, M., Tarokh, L., van Reen, E., Dorn, H., Velluti, R., Qu, W.-M., Huang, Z.-L., Hayaishi, O., Pedemonte, M., Drexler, D., Pol-Fernández, D., Bernhardt, V., Lopez, C., Rodriguez-Servetti, Z., Romanowski, C., Polta, S., Yassouridis, A., Abe, T., Takahashi, K., Koyama, Y., Kayama, Y., Lin, J.-S., Sakai, K., Gulia, K., Karashima, A., Shimazaki, M., Katayama, N., Nakao, M., Winsky-Sommerer, R., Knapman, A., Tobler, I., Altena, E., Sanz-Arigita, E., Chang, F.-C., Lu, C.-Y., Yi, P.-L., Hsiao, Y.-Z., Lowden, A., Nilsson, J., Hillert, L., Wiholm, C., Kuster, N., Arnetz, B., Szameitat, A., Shen, S., Daurat, A., Tiberge, M., Sok, N., D’Ortho, M. P. I. A., Karasinsky, P., Kohlmeier, K., Wess, J., Leonard, C., Kristensen, M., Kalinchuk, A., Porkka-Heiskanen, T., Mccarley, R. W., Basheer, R., Aizawa, R., Sunahara, H., Abe, S.-I., Iwaki, S., Houjyou, M., Satoh, M., Suda, H., Kheirandish-Gozal, L., Gozal, D., Walker, P., Noa, A., O’Driscoll, D., Ng, M., Yang, J., Davey, M., Anderson, V., Trinder, J., Horne, R., Sands, S., Kelly, V., Sia, K., Edwards, B., Skuza, E., Davidson, M., Berger, P. H. I. L. I. P., Wilkinson, M., Sánchez-Narváez, F., Gutiérrez, R., Camacho, L., Anaya, E., García-Campos, E., Labra, A., Domínguez, G., García-Polo, L., Haro, R., Verginis, N., Nixon, G., Baumert, M., Pamula, Y., Mihai, R., Wawurszak, M., Smith, N., Yiallourou, S., Andrew Ramsden, C., Williamson, B., Blecher, G., Teng, A., Dakin, C. Y. N., Yuil, M., Harris, M., Sadasivam, S., Bennison, J., Galland, B., Dawes, P., Taylor, B., Norman, M., Edwards, N., Harrison, H., Kol, C., Sullivan, C., Valladares, E., Macey, P., Kumar, R., Woo, M., Harper, R., Alger, J., Mcnamara, D., Tang, J., Goh, A., Teoh, O. H., Chiang, W. C., Chay, O. M., Marie Salvini, A., Riben, C., Blanck, A.-S., Marklund, M., Tourneux, P., Cardot, V., Leke, A., Iqbal, S. M., (Gus) Cooper, D., Witmans, M., Rodger, K., Thevasagayam, R., El-Hakim, H., Hill, C. M., Baya, A., Bucks, R., Kirkham, F., Virues-Ortega, J., Baldeweg, T., Paul, A., Hogan, A., Goodwin, J., Silva, G., Kaemingk, K., Sherrill, D., Morgan, W., Fregosi, R., Quan, S., Evans, C., Maclean, J., Waters, K., Fitzsimmons, D., Hayward, P., Fitzgerald, D., Terrill, G., O’Connell, A., Vannan, K., Richardson, H., Poluektov, M., Levin, I., Snegodskaya, M., Kolosova, N., Geppe, N., Nixon, G. Michelle, Thompson, J., Yhan, D., Becroft, D., Clark, P., Robinson, E., Waldie, K., Wild, C., Black, P., Stone, K., Britton, W., Chaves, Claudia, Tinoco, C., Goncalves, C., Ferreira, E., Santos, H., Boloto, J., Duarte, L., Paine, S., Wright, H., Slater, A., Rosen, G., Telliez, Frédéric, Djeddi, D., Kongolo, G., Degrugilliers, L., Horton, J., Buscemi, N., Vandermeer, B., Owens, J., Klassen, T., Gordon, J., King, N., Tripp, G., Oka, Y., Suzuki, S., de Lemos, M. C., Gonzaga, F. G., Shah, M. L., Bittencourt, L., Oliveira, L. V. Franco, Elshoff, J.-P., Braun, M., Andreas, J.-O., Strauss, B., Horstmann, R., Ahrweiler, S., Goldammer, N., Wada, M., Matsumoto, N., Rahman, M. D., Xu, X.-H., Makino, Y., Hashimoto, K., Zhang, M., Sastre, J.-P., Buda, C., Anaclet, C., Ohtsu, H., Danober, L., Desos, P., Cordi, A., Roger, A., Jacquet, A., Rogez, N., Thomas, J.-Y., Krentner, M., Boutin, J., Audinot-Bouchez, V., Baumann, C., Valko, P., Uhl, M., Hersberger, M., Rupp, T., Uchiyama, N., Nakamura, N., Konishi, T., Mcgrath, P., Fujiki, N., Tokunaga, J., Iijima, S., Nishino, S., Catherine, B.-R., Lely, F., Ralf, K., Oliver, N., François, J., Francois, J., Cedric, F., Changbin, Q., Patrick, H., Homanics, G., Heussler, H., Norris, R., Pache, D., Charles, B., Mcguire, T., Shelton, J., Bonaventure, P., Kelly, L., Aluisio, L., Lovenberg, T., Atack, J., Dugovic, C., Shapiro, C., Shen, J., Trajanovic, N., Chien, J., Verma, M., Fish, V., Wheatley, J., Amis, T., Alexiou, T., Wild, J., Bjursell, A., Solin, P., Sato, S., Matsubuchi, N., Gingras, M.-A., Labrosse, M., Chevrier, É, Lageix, P., Guay, M.-C., Braun, C., Godbout, R., Fatim, E. H., Loic, D., Stephane, D., Nathalie, L., Stéphane, D., Alain, G., Wiâm, R., Koabyashi, T., Tomita, S., Ishikawa, T., Manadai, O., Arakawa, K., Siato, Y., Bassi, A., Ocampo, A., Estrada, J., Blyton, D., O’Keeffe, K., Galletly, D., Larsen, P., Amatoury, J., Bilston, L., Kairaitis, K., Stephenson, R., Chu, K., Sekiguchi, Y., Suzuki, N., Yasuda, Y., Kodama, T., Honda, Y., Hsieh, K.-C., Lai, Y.-Y., Bannai, M., Kawai, N., Amici, R., Baracchi, F., Cerri, M., Del Sindaco, E., Dentico, D., Jones, C. A., Luppi, M., Martelli, D., Perez, E., Tazaki, M., Katayose, Y., Yasuda, K., Tokuyama, K., Maddison, K., Platt, P., Kirkness, J., Ware, J. C., May, J., Rosenthal, T., Park, G., Guibert, M., Allen, R. W., Cetin, T., Roman, V., Mollicone, D., Crummy, F., Cameron, P., Swann, P., Kossman, T., Taggart, F., Kandala, N.-B., Currie, A., Peile, E., Stranges, S., Marshall, N., Peltonen, M., Stenlof, K., Hedner, J., Sjostrom, L., Anderson, C., Platten, C., Jordan, K., Horne, J., Bjorkum, A., Kluge, B., Braseth, T., Gurvin, I., Kristensen, T., Nybo, R., Rosendahl, K., Nygaard, I., Biggs, S., Dollman, J., Kennedy, J. D., Martin, A. J., Haghighi, K. S., Bakht, N., Hyde, M., Harris, E., Zerouali, Y., Hosein, A., Jemel, B., Dodd, M., Rogers, N., Andersen, M., Martins, R., Alvarenga, T., Antunes, I., Papale, L., Killgore, W. S., Axelsson, J., Lekander, M., Ingre, M., Brismar, K., Dorrian, J., Ferguson, S., Jones, C., Buxton, O., Marcelli, E., Phipps-Nelson, J. O., Teixeira, L. R., de Castro Moreno, C., Turte, S. L., Nagai, R., do Rosário Dias De Oliveira Latorre, M., Marina, F., Paterson, J., Jackson, M., Johnston, P., Papafotiou, K., Croft, R., Dawson, S., Leenaars, C., Sandberg, H., Joosten, R., Dematteis, M., Feenstra, M., Wehrle, R., Rieger, M., Widmann, A., Dietl, T., Philipp, S., Wetter, T., Drummond, S., Czisch, M., Cairns, A., Lebourgeois, M., Harsh, J., Baulk, S., Vakulin, A., Catcheside, P., Antic, N., Mcevoy, D., Orff, H., Salamat, J., Meloy, M. J., Caron, A., Kostela, J., Purnell, M., Feyer, A.-M., Herbison, P., Saaresranta, T., Aittokallio, J., Karppinen, N., Toikka, J., Polo, O., Sallinen, M., Haavisto, M.-L., Hublin, C., Kiti, M., Jussi, V., Mikko, H., Chuah, L., Chee, M., Borges, F., Fischer, F., Moreno, C., Soares, N., Fonseca, M., Smolensky, M., Sackett-Lundeen, L., Haus, E., Nagata, N., Michael, N., Siccoli, M., Rogers, A., Hwang, W.-T., Scott, L., Dean, G., Geissler, E., Ametamey, S., Treyer, V., Wyss, M., Achermann, P., Schubiger, P., Theorell-Haglöw, J., Berne, C., Janson, C., Svensson, M., Lindberg, E., Caruso, H., Avinash, D., Minkel, J., Thompson, C., Wisor, J., Gerashchenko, D., Smith, K., Kuan, L., Pathak, S., Hawrylycz, M., Jones, A., Kilduff, T., Bergamo, C., Ecker, A., William, J., Niyogi, S., Coble, M., Goel, N., Lakhtman, L., Horswill, M., Whetton, M., Chambers, B., Signal, L., van Den Berg, M., Gander, P., Polotsky, V., Savransky, V., Bevans, S., Nanayakkara, A., Li, J.-G., Smith, P., Torbenson, M., Stockx, E., Brodecky, V., Berger, P., Chung-Mei Lam, J., Rial, R., Roca, C., Garau, C., Akaarir, M., Mccoy, J., Ward, C., Connolly, N., Tartar, J., Brown, R., Carberry, J., Bradford, A., O’Halloran, K., Mcguire, M., Nacher, M., Serrano-Mollar, A., Navajas, D., Farre, R., Montserrat, J., Fenik, V., Rukhadze, I., Kubin, L., Sivertsen, B., Overland, S., Mykletun, A., Czira, M., Fornádi, K., Lindner, A., Szeifert, L., Szentkirályi, A., Mucsi, I., Molnár, M., Novák, M., Zoller, R., Chin, K., Takegami, M., Oga, T., Nakayama-Asida, Y., Wakamura, T., Mishima, M., Fukuhara, S., Shepherd, K., Keir, G., Rixon, K., Makarie-Rofail, L., Unger, G., Svanborg, E., Harder, L., Sarberg, M., Broström, A., Josefsson, A., Herrera, A., Aguilera, L., Diaz, M., Fedson, A., Hung, J., Williams, C., Love, G., Middleton, S., Vermeulen, W., Middleton, P., Steinfort, D., Goldin, J., Eritaia, J., Dionysopoulos, P., Irving, L., Ciftci, T. U., Kokturk, O., Demirtas, S., Kanbay, A., Tavil, Y., Bukan, N., Demritas, S., Olsen, S., Douglas, J., Oei, T., Williams, S., Leung, S., Starmer, G., Lee, R., Chan, A., Dungan, G., Cistulli, P., Zeng, B., Bansal, A., Patial, K., Vijayan, V. K., Sonka, K., Fialova, L., Svarcova, J., Volna, J., Jiroutek, P., Pretl, M., Bartos, A., Hasegawa, R. A., Sasanabe, R., Nomura, A., Morita, M., Hori, R., Ohkura, Y., Shiomi, T. T., Collins, A., Jerums, G., Hare, D., Panagiotopoulos, S., Weatherhead, B., Bailey, M., Neil, C., Goldsworthy, U., Hill, C., Valencia-Flores, M., Resendiz, M., Juarez, S., Castano, A., Santiago, V., Aguilar, C., Ostrosky, F., Krum, H., Kaye, D., Neves, C., Decio, M., Monteiro, M., Cintra, F., Poyares, D., Viegas, C., Silva, C., Oliveira, H., Peixoto, T., Mikami, A., Watanabe, T., Kumano-Go, T., Adachi, H., Sugita, Y., Takeda, M., Oktay, B., Firat, H., Akbal, E., Ardic, S., Paim, S., Santos, R., Barrreto, A., Whitmore, H., Imperial, J., Temple, K., Rue, A., Hoffman, L., Liljenquist, D., Kazsa, K., Pavasovic, M., Copland, J., Ho, M., Jayamaha, J., Peverill, R., Hii, S., Hensley, M., Rowland, S., Windler, S., Johansson, M., Eriksson, P., Peker, Y., Råstam, L., Lindblad, U., Grote, L., Zou, D., Radlinski, J., Eder, D., Plens, C. M., Garcia Gonzaga, F. M., Farias Sa, P., Franco Oliveira, L. V., Faria Sa, P., Yoon, I.-Y., Chung, S., Hee Lee, C., Kim, J.-W., Faludi, B., Wang, X., Li, Q., Wan, H., Li, M., Pallayova, M., Donic, V., Tomori, Z., Ioacara, S., Olech, T., Mccallum, C., Bowes, M., Bowes, J., Chia, M., Gilbert, S. S., Sajkov, D., Teichtahl, H., Stevenson, I., Cunnington, D., Kalman, J., Szaboova, E., Higami, S., Kryger, M., Higami, Y., Suzuki, C., Kitano, H., Carin, S., Olof, S., Yngve, G., Gösta, B., Carlberg, B., Stenlund, H., Franklin, K. A., Oliveira, A., Vasconcelos, L., Martinez, D., Goncalves, S. C., Gus, M., Silva, E. O. A., Fuchs, S. C., Fuchs, F. D., Li, A., Au, J., Ho, C., Sung, R., Wing, Y., Tada, H., Terada, N., Togawa, K., Nakagawa, Y., Kishida, K., Kihara, S., Hirata, A., Sonoda, M., Nishizawa, H., Nakamura, T., Shimomura, I., Funahashi, T., Andrewartha, P., Sasse, A., Becker, M., Troester, N., Olschewski, H., Lisamayerkard, L., Glos, M., Blau, A., Peter, J.-G., Chesworth, W., Wilson, G., Piper, A., Chuang, L.-P., Lin, S.-W., Wang, C.-J., Li, H.-Y., Chou, Y.-T., Fu, J.-Y., Liao, Y.-F., Tsai, Y.-H., Chan, K., Laks, L., Nishibayashi, M., Miyamoto, M., Miyamoto, T., Hirata, K., Hoever, P., De Haas, S., Chiossi, E., Van Gerven, J., Dingemanse, J., Winkler, J., Cavallaro, M., Narui, K., Kasai, T., Dohl, T., Takaya, H., Kawana, F., Ueno, K., Panjwani, U., Thakur, L., Anand, J. P., Banerjee, P. K., Leigh, M., Paduch, A., Armstrong, J., Sampson, D., Kotajima, F., Mochizuki, T., Lorr, D., Harder, H., Chesworth, M., Becker, H., Abd-Elaty, N. M., Elprince, M., Ismail, N., Elserogi, W., Yeo, A., George, K., Thomson, K., Stadler, D., Bradley, J., Paul, D., Schwartz, A., Hagander, L., Harlid, R., Hultcrantz, E., Haraldsson, P., Cho, J.-G., Narayan, J., Nagarajah, M., Perri, R., Johnson, P., Burgess, K., Chau, N., Mcevoy, R. D., Arnardottir, E. S., Thorleifsdottir, B., Olafsson, I., Gislason, T., Tsuiki, S., Fujimatsu, S., Munezawa, T., Sato, Y., Subedi, P., Ainslie, P., Topor, Z., Whitelaw, W., Chan, M., So, H., Lam, H., Ng, S., Chan, I., Lam, C., Saigusa, H., Higurashi, N., He, Z. M., Cui, X. C., Li, J., Dong, X., Lv, Y., Zhou, M., Han, X., An, P., Wang, L., Macey, P. M., Serber, S., Cross, R., Yan-Go, F., Marshall, M., Rees, D., Lee, S. H., Ho Cho, J. I., Shin, C., Lee, J. Y., Kwon, S. Y., Kim, T.-H., Vedam, H., Barnes, D., Walter, H., Karin, J., Hermann, P., Belyavskiy, E., Galitsyn, P., Arbolishvili, G., Litvin, A., Chazova, I., Mareev, V., Ramar, K., Khan, A., Gay, P., Strömberg, A., Ulander, M., Fridlund, B., Mårtensson, J., Yee, B., Desai, A., Buchanan, P., Crompton, R., Melehan, K., Wong, P., Tee, A., Ng, A., Darendeliler, M. A., Ye, L., Maislin, G., Hurley, S., Mccluskey, S., Weaver, T., Yun, C.-H., Ji, K.-H., Ahn, J. Y., Lee, H.-W., Zhang, X., Yin, K., Zhaofang, G., Chong, L., Navailles, B., Zenou, E., Cheze, L., Pignat, J.-C., Tang, T., Remmers, J., Vasilakos, K., Denotti, A., Gilholme, J., Castronovo, V., Marelli, S., Aloia, M., Fantini, M. L., Kuo, T., Manconi, M., Zucconi, M., Ferini-Strambi, L., Livia Fantini, M., Giarolli, L., Oldani, A., Lee, Y., Trenell, M., Berend, N., Wang, M., Liang, Z., Lei, F., Komada, I., Nishikawa, M., Sriram, K., Mignone, L., Antic, R., Fujiwara, K., Beaudry, M., Gauthier, L., Laforte, M., Lavigne, G., Wylie, P., Orr, W., Grover, S., Geisler, P., Engelke, E., Cossa, G., Veitch, E., Brillante, R., Mcardle, N., Murphy, M., Singh, B., Gain, K., Maguire, C., Mutch, S., Brown, S., Asciuto, T., Newsam, C., Fransson, A., Ísacsson, G., Tsou, M.-C., Hsu, S.-P., Almendros, I., Acerbi, I., Vilaseca, I., Dcruz, O., Vaughn, B., Muenzer, J., Lacassagne, L., Montemayor, T., Roch-Paoli, J., Qian, J., Petocz, P., Chan, M. R., Munro, J., Zimmerman, M., Stanchina, M., Millman, R., Cassel, W., Ploch, T., Loh, A., Koehler, U., Jerrentrup, A., Greulich, T., Doyle, G., Pascoe, T., Jorgensen, G., Baglioni, C., Lombardo, C., Espie, C., Violani, C., Edell-Gustafsson, U., Swahn, E., Ejdeback, J., Tygesen, H., Johansson, A., Neckelmann, D., Hilde Nordhus, I., Zs-Kovács, Á., Vámos, E., Zs-Molnár, M., Maisuradze, L., Gugushvili, J., Darchia, N., Gvilia, I., Lortkipanidze, N., Oniani, N., Wang-Weigand, S., Mayer, G., Roth-Schechter, B., Hsu, S.-C., Yang, C.-M., Liu, C.-Y., Ito, H., Omvik, S., Nordhus, I. H., Farber, R., Scharf, M., Harris-Collazo, R., Pereira, J., Andras, S., Ohayon, M., David, B., Morgan, K., Voorn, T., Vis, J., Kuijer, J., Fortier-Brochu, E., Beaulieu-Bonneau, S., Ivers, H., Morin, C., Beaulieu-Benneau, S., Harris, J., Bartlett, D., Paisley, L., Moncada, S., Toelle, B., Bonnet, M. H., Arand, D., Bonnet, J., Bonnet, M., Doi, Y., Edéll-Gustafsson, U., Strijers, R., Fernando, A., Arroll, B., Warman, G., Funakura, M., Shikano, S., Unemoto, Y., Fujisawa, M., Hong, S.-C., Jeong, J.-H., Shin, Y.-K., Han, J.-H., Lee, S.-P., Lee, J.-H., Mignot, E., Nakajima, T., Hayashida, K., Honda, M., Ardestani, P., Etemadifar, M., Nejadnik, H., Maghzi, A. H., Basiri, K., Ebrahimi, A., Davoodi, M., Peraita-Adrados, R., Vicario, J. L., Shin, H.-B., Marti, I., Carriero, L., Fulda, S., Beitinger, P., Pollmacher, T., Lam, J. S. P., Fong, S. Y. Y., Tang, N. L. S., Ho, C. K. W., Li, A. M. C., Wing, Y. K., Guilleminault, C., Black, J., Wells, C., Kantor, S., Janisiewicz, A., Scammell, T., Tanaka, S., Smith, A., Neufing, P., Gordon, T., Fuller, P., Gompf, H., Pedersen, N., Saper, C., Lu, J., Sasai, T., Donjacour, C., Fronczek, R., Le Cessie, S., Lammers, G. J., van Dijk, J. G., Hayashi-Ogawa, Y., Okuda, M., Lam, V. K.-H., Chen, A. L., Ho, C. K.-W., Wing, Y.-K., Lehrhaft, B., Brilliante, R., van Der Zande, W., Overeem, S., van Dijk, G., Lammers, J. G., Opazo, C. J., Jeong, D.-U., Sung, Y. H., Lyoo, I. K., Takahashi, Y., Murasaki, M., Bloch, K., Jung, H., Dahab, M. M., Campos, T. F., Mccabe, S., Maravic, K., Wiggs, L., Connelly, V., Barnes, J., Saito, Y., Ogawa, M., Murata, M., Nadig, U., Rahman, A., Aritake, K., D’Cruz, O., Suzuki, K., Kaji, Y., Takekawa, H., Nomura, T., Yasui, K., Nakashima, K., Bahammam, A., Rab, M. G., Owais, S., Alsuwat, K., Hamam, K., Zs, M., Boroojerdi, B., Giladi, N., Wood, D., Sherman, D., Chaudhuri, R., Partinen, M., Abdo, F., Bloem, B., Kremer, B., Verbeek, M., Cronlein, T., Mueller, U., Hajak, G., Zulley, J., Namba, K., Li, L., Mtsuura, M., Kaneita, Y., Ohida, T., Cappeliez, B., Moutrier, R., De, S., Dwivedi, S., Chambers, D., Gabbay, E., Watanabe, A., Valle, C., Kauati, A., Watanabe, R., Chediek, F., Botte, S., Azevedo, E., Kempf, J., Cizza, G., Torvik, S., Brancati, G., Smirne, N., Bruni, A., Goff, E., Freilich, S., Malaweera, A., Simonds, A., Mathias, C., Morrell, M., Rinsky, B., Fonarow, G., Gradinger, F. P., Boldt, C., Geyh, S., Stucki, A., Dahlberg, A., Michel, F., Savard, M.-H., Savard, J., Quesnel, C., Hirose, K., Takahara, M., Mizuno, K., Sadachi, H., Nagashima, Y., Yada, Y., Cheung, C.-F., Lau, C., Lai, W., Sin, K., Tam, C., Hellgren, J., Omenaas, E., Gíslason, T., Jögi, R., Franklin, K., Torén, K., Wang, F., Kadono, M., Shigeta, M., Nakazawa, A., Ueda, M., Fukui, M., Hasegawa, G., Yoshikawa, T., de Niet, G., Tiemens, B., Lendemeijer, B., Hutschemaekers, G., Gauthier, A.-K., Chevrette, T., Chevrier, E., Bouvier, H., Parry, B., Meliska, C., Nowakowski, S., Lopez, A., Martinez, F., Sorenson, D., Lien, M. L., Lattova, Z., Maurovich-Horvat, E., Nia, S., Pollmächer, T., Poulin, J., Chouinard, S., Stip, E., Guillem, F., Venne, D., Caouette, M., Lamont, M.-E., Lázár, A., Lázár, Z., Bíró, A., Gyõri, M., Tárnok, Z., Prekop, C., Gádoros, J., Halász, P., Bódizs, R., Okun, M., Hanusa, B., Hall, M., Wisner, K., Pereira, M., Kumar, R. A. J. E. S. H., Macey, P. A. U. L., Woo, M. A. R. Y., Serber, S. T. A. C. Y., Valladares, E. D. W. I. N., Harper, R. E. B. E. C. C. A., Harper, R. O. N. A. L. D., Puttonen, S., Härmä, M., Vahtera, J., Kivimäki, M., Lamarche, L., Hemmeter, U. M., Thum, A., Rocamora, R., Giesler, M., Haag, A., Dodel, R., Krieg, J. C., Shechter, A., L’Esperance, P., Boivin, D. B., Vu, M.-T., and Richards, H.

Published
2007
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24. Linkage mapping in populations with karyotypic rearrangements

Author

Livingstone, K.D., Churchill, G., and Jahn, M.K.

Subjects
Chromosome mapping -- Research, Genetic research -- Case studies, Karyotypes -- Research, Biological sciences
Abstract

A new study investigates the role of karyotypic rearrangements on the construction of molecular genetic maps.

Published
2000

28. Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor

Author

Saitou, M., primary, Resendez, S., additional, Pradhan, A.J., additional, Wu, F., additional, Lie, N.C., additional, Hall, N.J., additional, Zhu, Q., additional, Reinholdt, L., additional, Satta, Y., additional, Nakagome, S., additional, Hanchard, N.A., additional, Churchill, G., additional, Lee, C., additional, Atilla-Gokcumen, G.E., additional, Mu, X., additional, and Gokcumen, O., additional

Published
2019
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33. Oxford Lithium Trial (OxLith) of the early affective, cognitive, neural and biochemical effects of lithium carbonate in bipolar disorder: study protocol for a randomised controlled trial

Author

Saunders, K, Cipriani, A, Rendell, J, Attenburrow, M, Nelissen, N, Bilderbeck, A, Vasudevan, S, Churchill, G, Goodwin, G, Nobre, A, Harmer, C, Harrison, P, and Geddes, J

Subjects
Adult, Male, Time Factors, Medicine (miscellaneous), Neuropsychological Tests, Lithium, Young Adult, Oxford Lithium Trial, Cognition, Clinical Protocols, Double-Blind Method, Lithium Carbonate, Antimanic Agents, Humans, Pharmacology (medical), Prospective Studies, Mood instability, rct, Psychiatric Status Rating Scales, bipolar disorder, Experimental medicine, Brain, Magnetoencephalography, Magnetic Resonance Imaging, Affect, Treatment Outcome, England, Gene Expression Regulation, Research Design, Female, Oxford Lithium Trial, bipolar disorder, study protocol, rct, Biomarkers, study protocol
Abstract

Background Despite lithium’s being the most effective drug for bipolar disorder and in clinical use for decades, we still know very little about its early effects relevant to its mode of action. Methods/design The Oxford Lithium Trial is a double-blind, randomised, placebo-controlled study of 6-week lithium treatment in participants with bipolar disorder and mood instability. Its aim is to identify early clinical, neurocognitive and biological effects. Participants (n = 40) will undergo an intensive battery of multi-modal investigations, including remote monitoring of mood, activity and physiology, as well as cognitive testing, fMRI and magnetoencephalography, together with biochemical and gene expression measurements to assess renal, inflammatory and circadian effects. Discussion The findings derived from this trial may be of value in predicting subsequent therapeutic response or side effects, not only relevant to the use of lithium but also providing a potential signature to help in more rapid evaluation of novel mood stabilisers. In this respect, OxLith is a step towards the development of a valid experimental medicine model for bipolar disorder. Trial registration ISRCTN91624955. Registered on 22 January 2015.

Published
2016

37. Two pore channels (TPC2s) and nicotinic acid adenine dinucleotide phosphate (NAADP) at lysosomal-sarcoplasmic reticular junctions contribute to acute and chronic β-adrenoceptor signaling in the heart

Author

Capel, R, Bolton, E, Lin, W, Aston, D, Wang, Y, Liu, W, Wang, X, Burton, R, Bloor-Young, D, Shade, K, Ruas, M, Parrington, J, Churchill, G, Lei, M, Galione, A, and Terrar, D

Subjects
Male, Mice, Knockout, calcium intracellular release, cardiac hypertrophy, Myocardium, Guinea Pigs, heart, nicotinic acid adenine dinucleotide phosphate (NAADP), endoplasmic reticulum (ER), calcium imaging, Mice, Sarcoplasmic Reticulum, Receptors, Adrenergic, beta, lysosome, Animals, Calcium Channels, Lysosomes, Ca2+/calmodulin-dependent protein kinase II (CaMKII), NADP, Signal Transduction, adrenergic receptor
Abstract

Background: The Ca2+-releasing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) acts via lysosomal two-pore channels (TPC2). Results: Tpcn2−/− cardiac myocytes showed reduced acute responses to β-adrenoreceptor stimulation and chronically reduced cardiac hypertrophy and arrhythmogenesis. Conclusion: Acute and chronic effects of cardiac β-adrenoreceptor stimulation depend on NAADP acting via TPC2 in lysosomes. Significance: NAADP/TPC2 signaling pathways offer new strategies for cardiac therapeutics., Ca2+-permeable type 2 two-pore channels (TPC2) are lysosomal proteins required for nicotinic acid adenine dinucleotide phosphate (NAADP)-evoked Ca2+ release in many diverse cell types. Here, we investigate the importance of TPC2 proteins for the physiology and pathophysiology of the heart. NAADP-AM failed to enhance Ca2+ responses in cardiac myocytes from Tpcn2−/− mice, unlike myocytes from wild-type (WT) mice. Ca2+/calmodulin-dependent protein kinase II inhibitors suppressed actions of NAADP in myocytes. Ca2+ transients and contractions accompanying action potentials were increased by isoproterenol in myocytes from WT mice, but these effects of β-adrenoreceptor stimulation were reduced in myocytes from Tpcn2−/− mice. Increases in amplitude of L-type Ca2+ currents evoked by isoproterenol remained unchanged in myocytes from Tpcn2−/− mice showing no loss of β-adrenoceptors or coupling mechanisms. Whole hearts from Tpcn2−/− mice also showed reduced inotropic effects of isoproterenol and a reduced tendency for arrhythmias following acute β-adrenoreceptor stimulation. Hearts from Tpcn2−/− mice chronically exposed to isoproterenol showed less cardiac hypertrophy and increased threshold for arrhythmogenesis compared with WT controls. Electron microscopy showed that lysosomes form close contacts with the sarcoplasmic reticulum (separation ∼25 nm). We propose that Ca2+-signaling nanodomains between lysosomes and sarcoplasmic reticulum dependent on NAADP and TPC2 comprise an important element in β-adrenoreceptor signal transduction in cardiac myocytes. In summary, our observations define a role for NAADP and TPC2 at lysosomal/sarcoplasmic reticulum junctions as unexpected but major contributors in the acute actions of β-adrenergic signaling in the heart and also in stress pathways linking chronic stimulation of β-adrenoceptors to hypertrophy and associated arrhythmias.

Published
2015

38. Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A

Author

European Commission, Ministerio de Economía y Competitividad (España), Michael J. Fox Foundation for Parkinson's Research, Fernández, B., Fernández, Elena, Gómez-Suaga, P., Gil, Fernando, Molina Villalba, Isabel, Ferrer, Isidro, Patel, S., Churchill, G. C., Hilfiker, Sabine, European Commission, Ministerio de Economía y Competitividad (España), Michael J. Fox Foundation for Parkinson's Research, Fernández, B., Fernández, Elena, Gómez-Suaga, P., Gil, Fernando, Molina Villalba, Isabel, Ferrer, Isidro, Patel, S., Churchill, G. C., and Hilfiker, Sabine

Abstract

Various neurodegenerative disorders are associated with increased brain iron content. Iron is known to cause oxidative stress, which concomitantly promotes cell death. Whereas endolysosomes are known to serve as intracellular iron storage organelles, the consequences of increased iron on endolysosomal functioning, and effects on cell viability upon modulation of endolysosomal iron release remain largely unknown. Here, we show that increasing intracellular iron causes endolysosomal alterations associated with impaired autophagic clearance of intracellular protein aggregates, increased cytosolic oxidative stress and increased cell death. These effects are subject to regulation by NAADP, a potent second messenger reported to target endolysosomal TPCNs (2-pore channels). Consistent with endolysosomal iron storage, cytosolic iron levels are modulated by NAADP, and increased cytosolic iron is detected when overexpressing active, but not inactive TPCNs, indicating that these channels can modulate endolysosomal iron release. Cell death triggered by altered intralysosomal iron handling is abrogated in the presence of an NAADP antagonist or when inhibiting RAB7A activity. Taken together, our results suggest that increased endolysosomal iron causes cell death associated with increased cytosolic oxidative stress as well as autophagic impairments, and these effects are subject to modulation by endolysosomal ion channel activity in a RAB7A-dependent manner. These data highlight alternative therapeutic strategies for neurodegenerative disorders associated with increased intracellular iron load.

Published
2016

40. Quantitative Trait Locus Mapping Methods for Diversity Outbred Mice

Author

Simecek, P., Churchill, G. A., Palmer, A., Chesler, E. J., Broman, K. W., Svenson, K. L., Valdar, W., Cheng, R., Shabalin, A., Goodwin, N., Gatti, D. M., Pomp, D., and Wu, L.-Y.

Abstract

Genetic mapping studies in the mouse and other model organisms are used to search for genes underlying complex phenotypes. Traditional genetic mapping studies that employ single-generation crosses have poor mapping resolution and limit discovery to loci that are polymorphic between the two parental strains. Multiparent outbreeding populations address these shortcomings by increasing the density of recombination events and introducing allelic variants from multiple founder strains. However, multiparent crosses present new analytical challenges and require specialized software to take full advantage of these benefits. Each animal in an outbreeding population is genetically unique and must be genotyped using a high-density marker set; regression models for mapping must accommodate multiple founder alleles, and complex breeding designs give rise to polygenic covariance among related animals that must be accounted for in mapping analysis. The Diversity Outbred (DO) mice combine the genetic diversity of eight founder strains in a multigenerational breeding design that has been maintained for >16 generations. The large population size and randomized mating ensure the long-term genetic stability of this population. We present a complete analytical pipeline for genetic mapping in DO mice, including algorithms for probabilistic reconstruction of founder haplotypes from genotyping array intensity data, and mapping methods that accommodate multiple founder haplotypes and account for relatedness among animals. Power analysis suggests that studies with as few as 200 DO mice can detect loci with large effects, but loci that account for

Published
2014
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41. Genetic Regulation of Zfp30, CXCL1, and Neutrophilic Inflammation in Murine Lung

Author

Aylor, D. L., Chines, P., Peck, B. C., Churchill, G. A., Carpenter, D. E., de Villena, F. P.-M., Rutledge, H., Ostrowski, L. E., Kelada, S. N. P., and Chesler, E. J.

Subjects
animal diseases, respiratory system, respiratory tract diseases
Abstract

Allergic asthma is a complex disease characterized in part by granulocytic inflammation of the airways. In addition to eosinophils, neutrophils (PMN) are also present, particularly in cases of severe asthma. We sought to identify the genetic determinants of neutrophilic inflammation in a mouse model of house dust mite (HDM)-induced asthma. We applied an HDM model of allergic asthma to the eight founder strains of the Collaborative Cross (CC) and 151 incipient lines of the CC (preCC). Lung lavage fluid was analyzed for PMN count and the concentration of CXCL1, a hallmark PMN chemokine. PMN and CXCL1 were strongly correlated in preCC mice. We used quantitative trait locus (QTL) mapping to identify three variants affecting PMN, one of which colocalized with a QTL for CXCL1 on chromosome (Chr) 7. We used lung eQTL data to implicate a variant in the gene Zfp30 in the CXCL1/PMN response. This genetic variant regulates both CXCL1 and PMN by altering Zfp30 expression, and we model the relationships between the QTL and these three endophenotypes. We show that Zfp30 is expressed in airway epithelia in the normal mouse lung and that altering Zfp30 expression in vitro affects CXCL1 responses to an immune stimulus. Our results provide strong evidence that Zfp30 is a novel regulator of neutrophilic airway inflammation.

Published
2014
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44. C57BL/6N Mutation in Cytoplasmic FMRP interacting protein 2 Regulates Cocaine Response

Author

Yoo, S.-H., Kourrich, S., Kumar, V., Huang, H. C., Churchill, G., Kim, K., Joseph, C., Bonci, A., Takahashi, J. S., Vitaterna, M. H., and Pardo-Manuel de Villena, F.

Abstract

The inbred mouse C57BL/6J is the reference strain for genome sequence and for most behavioral and physiological phenotypes. However the International Knockout Mouse Consortium uses an embryonic stem cell line derived from a related C57BL/6N substrain. We found that C57BL/6N has lower acute and sensitized response to cocaine and methamphetamine. We mapped a single causative locus and identified a non-synonymous mutation of serine to phenylalanine (S968F) in Cytoplasmic FMR interacting protein 2 (Cyfip2) as the causative variant. The S968F mutation destabilizes CYFIP2 and deletion of the C57BL/6N mutant allele leads to acute and sensitized cocaine response phenotypes. We propose CYFIP2 is a key regulator of cocaine response in mammals and present a framework to utilize mouse substrains to discover novel genes and alleles regulating behavior.

Published
2013
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45. Ebselen has lithium-like effects on central 5-HT2A receptor function.

Author

Antoniadou, I., Kouskou, M., Arsiwala, T., Singh, N., Vasudevan, S. R., Fowler, T., Cadirci, E., Churchill, G. C., and Sharp, T.

Subjects
LITHIUM, ANTIDEPRESSANTS, INOSITOL monophosphatase, G protein coupled receptors, ENZYMES
Abstract

Background and Purpose: Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in Gq -protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here, we investigated both ebselen and lithium in models of the 5-HT2A receptor, a Gq -protein coupled receptor involved in lithium's actions.Experimental Approach: 5-HT2A receptor function was assessed in mice by measuring the behavioural (head-twitches, ear scratches) and molecular (cortical immediate early gene [IEG] mRNA; Arc, c-fos, Egr2) responses to 5-HT2A receptor agonists. Ebselen and lithium were administered either acutely or repeatedly prior to assessment of 5-HT2A receptor function. Because lithium and 5-HT2A receptor antagonists augment the action of selective serotonin reuptake inhibitors (SSRIs), ebselen was tested for this activity by co-administration with the SSRI citalopram in microdialysis (extracellular 5-HT) experiments.Key Results: Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5-HT2A receptor agonist DOI. Repeated lithium also inhibited DOI-evoked behavioural and IEG responses. In comparison, a selective IMPase inhibitor (L-690330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR-A014418) did not. Finally, ebselen enhanced the increase in extracellular 5-HT induced by citalopram, and also increased regional brain 5-HT synthesis.Conclusions and Implications: Our data demonstrated lithium-mimetic effects of ebselen in different experimental models of 5-HT2A receptor function, probably mediated by IMPase inhibition. This evidence of lithium-like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorders, including as an antidepressant augmenting agent. [ABSTRACT FROM AUTHOR]

Published
2018
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46. Shape-based reprofiling of FDA-approved drugs for the H₁ histamine receptor

Author

Vasudevan, SR, Moore, J, Schymura, Y, and Churchill, G

Abstract

Reprofiling of existing drugs to treat conditions not originally targeted is an attractive means of addressing the problem of a decreasing stream of approved drugs. To determine if 3D shape similarity can be used to rationalize an otherwise serendipitous process, we employed 3D shape-based virtual screening to reprofile existing FDA-approved drugs. The study was conducted in two phases. First, multiple histamine H(1) receptor antagonists were identified to be used as query molecules, and these were compared to a database of approved drugs. Second, the hits were ranked according to 3D similarity and the top drugs evaluated in a cell-based assay. The virtual screening methodology proved highly successful, as 13 of 23 top drugs tested selectively inhibited histamine-induced calcium release with the best being chlorprothixene (IC(50) 1 nM). Finally, we confirmed that the drugs identified using the cell-based assay were all acting at the receptor level by conducting a radioligand-binding assay using rat membrane.

Published
2012

50. Acidic NAADP-sensitive calcium stores in the endothelium: agonist-specific recruitment and role in regulating blood pressure

Author

Brailoiu, G, Gurzu, B, Gao, X, Parkesh, R, Aley, P, Trifa, D, Galione, A, Dun, N, Madesh, M, Patel, S, Churchill, G, and Brailoiu, E

Abstract

Accumulating evidence implicates nicotinic acid adenine dinucleotide phosphate (NAADP) in the control of Ca(2+)-dependent functions. Little, however, is known concerning its role in the vascular endothelium, a major regulator of blood pressure. Here, we show that NAADP acetoxymethyl ester (NAADP-AM), a cell-permeant NAADP analog, increases cytosolic Ca(2+) concentration in aortic endothelial cells. We demonstrate that these signals and those evoked by acetylcholine are blocked by disrupting acidic organelles with bafilomycin A1. In contrast, Ca(2+) signals in response to thrombin are only partially inhibited by bafilomycin A1 treatment, and those to ATP were insensitive, suggesting that recruitment of acidic stores is agonist-specific. We further show that NAADP-evoked Ca(2+) signals hyperpolarize endothelial cells and generate NO. Additionally, we demonstrate that NAADP dilates aortic rings in an endothelium- and NO-dependent manner. Finally, we show that intravenous administration of NAADP-AM into anesthetized rats decreases mean arterial pressure. Our data extend the actions of NAADP to the endothelium both in vitro and in vivo, pointing to a previously unrecognized role for this messenger in controlling blood pressure.

Published
2010

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