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1. The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas

Author

Deng, Jinhai, Pan, Teng, Wang, Dan, Hong, Yourae, Liu, Zaoqu, Zhou, Xingang, An, Zhengwen, Li, Lifeng, Alfano, Giovanna, Li, Gang, Dolcetti, Luigi, Evans, Rachel, Vicencio, Jose M, Vlckova, Petra, Chen, Yue, Monypenny, James, Gomes, Camila Araujo De Carvalho, Weitsman, Gregory, Ng, Kenrick, McCarthy, Caitlin, Yang, Xiaoping, Hu, Zedong, Porter, Joanna C, Tape, Christopher J, Yin, Mingzhu, Wei, Fengxiang, Rodriguez-Justo, Manuel, Zhang, Jin, Tejpar, Sabine, Beatson, Richard, and Ng, Tony

Published
2024
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3. Telehealth-delivered cognitive rehabilitation for people with cognitive impairment as part of the post-COVID syndrome: protocol for a randomised controlled trial as part of the CICERO (Cognitive Impairment in Long COVID: Phenotyping and Rehabilitation) study

Author

Vanova, Martina, Patel, Aysha Mohamed Rafik, Scott, Iona, Gilpin, Gina, Manning, Emily N., Ash, Charlotte, Wittenberg, Philippa, Lim, Jason, Hoare, Zoe, Evans, Rachel, Bray, Nathan, Kipps, Christopher M., Devine, Ciara, Ahmed, Saliha, Dunne, Ross, Koniotes, Anna, Warren, Catherine, Chan, Dennis, and Suarez-Gonzalez, Aida

Published
2024
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4. Implementing and evaluating group interpersonal therapy for postnatal depression in Lebanon and Kenya—individually randomised superiority trial

Author

Fonagy, Peter, Chammay, Rabih El, Ngunu, Carol, Kumar, Manasi, Verdeli, Lena, Allison, Elizabeth, Anani, Ghida, Fearon, Pasco, Fouad, Fouad, Hoare, Zoe, Koyio, Lucina, Moore, Henrietta, Nyandigisi, Andrew, Pilling, Stephen, Sender, Hannah, Skordis, Jolene, Evans, Rachel, Jaoude, Gerard Joseph Abou, Madeghe, Beatrice, Maradian, Sandra Pardi Arsen, O’Donnell, Ciara, Simes, Elizabeth, Truscott, Alexandra, Wambua, Grace Nduku, and Yator, Obadia

Published
2024
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6. Inhibition of Transforming Growth Factor-β Improves Primary Renal Tubule Cell Differentiation in Long-Term Culture.

Author

Hunter, Kuniko, Larsen, Jaclyn, Love, Harold, Evans, Rachel, Zent, Roy, Harris, Raymond, Wilson, Matthew, Fissell, William, and Roy, Shuvo

Subjects
TGF-beta, bioartificial kidney, renal tubule cell, transforming growth factor beta, Animals, Humans, Cell Differentiation, Mammals, Receptors, Transforming Growth Factor beta, Renal Insufficiency, Transforming Growth Factor beta, Transforming Growth Factor beta1, Transforming Growth Factors
Abstract

Patient-oriented applications of cell culture include cell therapy of organ failure like chronic renal failure. Clinical deployment of a cell-based device for artificial renal replacement requires qualitative and quantitative fidelity of a cultured cell to its in vivo counterpart. Active specific apicobasal ion transport reabsorbs 90-99% of the filtered load of salt and water in the kidney. In a bioengineered kidney, tubular transport concentrates wastes and eliminates the need for hemodialysis, but renal tubule cells in culture transport little or no salt and water due to dedifferentiation that mammalian cells undergo in vitro thereby losing important cell-type specific functions. We previously identified transforming growth factor-β (TGF-β) as a signaling pathway necessary for in vitro differentiation of renal tubule cells. Inhibition of TGF-β receptor-1 led to active and inhibitable electrolyte and water transport by primary human renal tubule epithelial cells in vitro. Addition of metformin increased transport, in the context of a transient effect on 5-AMP-activated kinase phosphorylation. These data motivated us to examine whether increased transport was an idiosyncratic effect of SB431542, probe pathways downstream of TGF-β receptors possibly responsible for the improved differentiation, evaluate whether TGF-β inhibition induced a range of differentiated tubule functions, and to explore crosstalk between the effects of SB431542 and metformin. In this study, we use multiple small-molecule inhibitors of canonical and noncanonical pathways to confirm that inhibition of canonical TGF-β signaling caused the increased apicobasal transport. Hallmarks of proximal tubule cell function, including sodium reabsorption, para-amino hippurate excretion, and glucose uptake increased with TGF-β inhibition, and the specificity of the response was shown using inhibitors of each transport protein. We did not find any evidence of crosstalk between metformin and SB431542. These data suggest that the TGF-β signaling pathway governs multiple features of differentiation in renal proximal tubule cells in vitro. Inhibition of TGF-β by pharmacologic or genome engineering approaches may be a viable approach to enhancing differentiated function of tubule cells in vitro. Impact statement Cell therapy of renal failure requires qualitative and quantitative fidelity between in vitro and in vivo phenotypes, which has been elusive. We show that control of transforming growth factor-β signaling can promote differentiation of renal tubule cells grown in artificial environments. This is a key enabling step for cell therapy of renal failure.

Published
2023

7. Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial

Author

Jelley, Benjamin, Hughes, Tom, Evans, Mim, Esteban, Diego Garcia, Knibbs, Lucy, Broad, Lauren, Price, Rebecca, Griebel, Liz Hamer, Hewson, Sian, Thavanesan, Kamy, Mallon, Louise, Smith, Anna, White, Miranda, Zhang, Liqun, Clarke, Brian, Abousleiman, Youssif, Binnie, Lauren, Sim, Cai Hua, Castanheira, Margarida, Humphries, Fiona, Obarey, Sabaa, Feerick, Shez, Lee, Yee Chin, Lewis, Alex, Muhammad, Riham, Francia, Nina, Atang, Ndifreke, Banaras, Azra, Marinescu, Marilena, Ferdinand, Philip, Varquez, Resti, Ponce, Ida, Saxena, Surabhi, O'Brien, Eoin, Reyes, Juliana Delos, Mitchell-Douglas, Jennifer, Francis, Jobbin, Banerjee, Soma, Dave, Vaishali, Mashate, Sheila, Patel, Tulsi, Sekaran, Lakshmanan, Murad, Wahid, Asaipillai, Asokanathan, Sakthivel, Sethuraman, Tate, Margaret, Angus, Jane, Reid, Lisa, Fornolles, Caroline, Sundayi, Saul, Poolon, Lincy, Justin, Francis, Hunte, Sophy, Bhandari, Mohit, Kho, Jules, Cvoro, Vera, Parakramawansha, Ruwan, Couser, Mandy, Hughes, Hannah, Naqvi, Aaizza, Harkness, Kirsty, Richards, Emma, Howe, Jo, Kamara, Chris, Gardner, Jon, Bains, Harjit, Teal, Rachel, Joseph, Jeethu, Benjamin, Jithen, Al-Hussayni, Samer, Thomas, George, Robinson, Faye, Dixon, Lynn, Krishnan, Manju, Slade, Peter, Anjum, Tal, Storton, Sharon, Adie, Katja, Northcott, Keren, Morgan, Katie, Williams, Emilie, Chanashekar, Harinath, Maguire, Holly, Gabriel, Claire, Maren, Deborah, David, Hannah, Clarke, Sheron, Nagaratnam, Kiruba, Nelatur, Varun, Mannava, Neelima, Blasco, Lara, Devine, Joseph, Bathula, Rajaram, Gopi, Parvathy, Mehta, Niharika, Sreedevi Raj, Sreena, Teo, James, Sztriha, Laszio, Mah, Yee, Ankolekar, Sandeep, Sari, Beatrix, Tibajai, Maria, Morgan, Alicia, Recaman, Maria, Bayhonan, Samantha, Belo, Caroline, Finch, Sharon, Keenan, Samantha, Bowring, Angie, Shetty, Ashit, Chan, Siang, Gray, Lucy, Harrison, Thomas, Spooner, Oliver, Kinsella-Perks, Edward, Erumere, Esther, Sanders, Brittany, Sims, Don, Willmot, Mark, Littleton, Edward, Spruce, Elaine, Moody, Lisa, Sheriden, Christopher, Luxmore-Brown, Scott, Neal, Aoife, Beddows, Sophie, Tuna, Maria Assuncao, Misra, Amulya, Penn, Ruth, Mariampillai, Sonia, Anwar, Ijaz, Annamalai, Arunkumar, Whitehouse, Sarah, Shepherd, Lorna, Siddle, Elaine, Chatterjee, Kausik, Leason, Sandra, Davies, Angela, Marigold, Richard James, Frank, Sarah, Baird, Alix, Hannam-Penfold, Tomas, Inacio, Liliana, Smith, Simon, Eveson, David, Musarrat, Kashif, Khan, Shagufta, Harris, Tracy, Chowdhury, Muhibbur, Alam, Sajid, Jamieson, Elena, Anyankpele, Ebitare, Al Shalchi, Farah, Rivers, Vanessa, Bell, Stephanie, Francis, Rebecca, Beeby, Deborah, Finch, Jenny, Macleod, Mary Joan, Guzman-Gutierrez, German, Carter, Karla, Irvine, Janice, Gbadamoshi, Lukuman, Costa, Telma, Heirons, Sarah, Stoney, Hayley, Shaw, Louise, Choulerton, James, Catibog, Darwin, Sattar, Naweed, Myint, Min, Smith, Andy, Serac, Kwin, Emsley, Hedley, Sultan, Sulaiman, Gregary, Bindu, Brown, Allan, Mahmood, Afzal, Chattha, Navraj, Old, William, Pegg, Claire, Davey, Miriam, Page, Michelle, Sandhu, Banher, Phiri, Emily, Rashed, Khalid, Wilson, Elisabeth, Hindley, Esther, Board, Sarah, Antony, Sherly, Tanate, Alfonso, Davis, Michelle, Holland, Beth, Slater, Victoria, Fawcett, Michelle, England, Tim, Scott, James, Beavan, Jessica, Hedstrom, Amanda, Karunatilake, Dumin, Gillmain, Kimberley, Singh, Nishy, Hallows, Tracy, Barber, Mark, Yates, Luke, Micallef, Clayton, Esson, Derek, Meng Yu, Wai, Ming New, Benjamin Jaa, Matos, Alexandre, Burt, Clare, Cabrelli, Louise, Wilkie, Gillian, Meegada, Madana, Kirthivasan, Ramanathan, Fox, Caroline, Mead, Victoria, Lyle, Amanda, Saksena, Rajesh, Bakshi, Aashima, O'Kelly, Alison, Rehan, Jahanzeb, Ebueka, Osaretin, Cooper, Martin, Wynter, Inez, Smith, Susan, Kumar, Senthil, O'Brien, Linda, Parker, Cerrys, Parker, Emma, Khan, Numan, Patterson, Christopher, Maguire, Stuart, Quinn, Outi, Bellfield, Ruth, Behnam, Yousif, Costa, Janet, Padilla-Harris, Cheryl, Moram, Louise, Raza, Syed Abid, Tench, Helen, Sims, Tanya, McGuinness, Heather, Loosley, Ronda, Wolf-Roberts, Rebecca, Buddha, Sandeep, Salt, Irmak, Lewis, Kerry, Mavinamne, Sunanda, Ditchfield, Coleen, Dealing, Sharon, Shah, Alexander, Crossingham, Ginette, Mwadeyi, Memory, Kenton, Anthony, Omoregie, Faith, Abubakar, Saidu, Warwick, Allison, Hector, Gemma, Hassan, Ahamad, Veraque, Emelda, Farman, Michelle, Makawa, Linetty, Byrne, Anthony, Kirkham, Jackie, Blayney, Gareth, Selwyn, Jey, Kakar, Puneet, Al Khaddour, Mohammed, Dhami, Reena, Baker, Emelda, Esisi, Bernard, Clarkson, Emma, Fellowes, Dominic, Kresmir, Jergovic, Guyler, Paul, Ngo, David, Wijenayake, Indunil, Tysoe, Sharon, Galliford, Joanne, Harman, Paula, Garside, Mark, Badanahatti, Madhava, Riddell, Victoria, Gramizadeh, Gita, Dutta, Dipankar, Bajoriene, Milda, Erdogan, Hulya, Ward, Deborah, Doubal, Fergus, Samarasekera, Neshika, Risbridger, Sarah, MacRaild, Allan, Azim, Abul, Wood, Lisa, Tampset, Ruth, Shekhar, Raj, Rai, Umesh, Fuller, Tracy, Joshy, Aricsa, Nadar, Evelyn, Kini, Manohar, Ahmad, Syed, Robinson, Matthew, King, Lucia, Srinivasan, Venkatesan, Karwacka-Cichomska, Magdalena, Moore, Vicki, Smith, Kate, Kariyadil, Bincy, Kong, Kelvin, Hubbard, Kelly, Arif, Sarwat, Hasan, Muhammad, Temple, Natalie, Arcoria, Daniele, Horne, Zoey, Soe, Thandar, Wyllie, Hilary, Hacon, Christian, Sutherland, Helen, Menezes, Brian, Johnson, Venetia, Smyth, Nigel, Mehdi, Zehra, Tone, Ela, Bradley, Arian, Levell, Emma, Ekkert, Aleksandra, Mazzucco, Sara, McCafferty, Laura, Vonoven, Linda, Dewan, Suprita, Sridhar, Pagadala, Thomas, Jayne, Coetzee, Samantha, Icke, Becky, Williams, Jill, Saravanan, Narayanamoorthi, Bradley, Pamela, Gibson, Rebecca Marie, Antony, Jijimol, Ashraf, Imran, Mabuti, Jose, Kamundi, Charlotte, Patiola, Prasanna, Oakley, Naomi, Proeschel, Harold, Kelly, Debs, Longley, Wendy, Cave, Ashleigh, Ambrico, Carla, Black, Toby, Porretta, Elisa, Anthony, Alpha, Ragab, Suzanne, Dube, Judith, Kausar, Shahid, Gujjar, Abdullah, Abdullah, Mohammad, Kaur, Daljit, Gadapa, Naveen, Choudhary, Sumita, Nisar, Nabeela, Fawehinmi, Grace, Dunne, Karen, King, Sam, Kishore, Amit, Lee, Stephanie, Marsden, Tracy, Slaughter, Melanie, Cawley, Kathryn, Perez, Jane, Anderton, Peter, Soussi, Salem, Walstow, Deborah, Pugh, Rebecca, Manoj, Aravind, Fletcher, Glynn, Lopez, Paula, McCormick, Michael, Magee, Michael, Tallon, Grainne, McFarland, Denise, Cosgrove, Denise, Shinh, Naval, Metcalf, Kneale, Kostyuk, Alina, McDonald, Susan, Sayers, Sophie, Sayed, Walee, Abraham, Sam, Szabo, Gemma, Crosbie, Gareth, McIlmoyle, Jim, Fearon, Patricia, Courtney, Kerry, Tauro, Suzanne, Singh, Arun, Nair, Anand, Duberley, Stephen, Philip, Sheeba, Curley, Cath, Goddard, Wendy, Bridge, Luke, Willcoxson, Paul, Wanklyn, Peter, Owen, Jennifer, France, John, Reed, Bryony, Foulds, Angie, Richard, Bella, Parfitt, Louise, Affley, Brendan, Russo, Cristina, Dsouza, Margaret, Cruddas, Elizabeth, Hargroves, David, Rand, James, Shekar, Som, Bhat, Yaqoob, Marshall, Gail, Nash, Maxine, Ahmad, Nasar, Okoko, Blessing Oduh, Evans, Rachel, Taylor, Tegan, Dawson, Jesse, Colquhoun, Elizabeth, James, Christopher, Aguirre, Carlos, MacPhee, Catherine, Phipps, Janet, Ispoglou, Sissi, Hayes, Anne, Werring, David J, Dehbi, Hakim-Moulay, Ahmed, Norin, Arram, Liz, Best, Jonathan G, Balogun, Maryam, Bennett, Kate, Bordea, Ekaterina, Caverly, Emilia, Chau, Marisa, Cohen, Hannah, Cullen, Mairead, Doré, Caroline J, Engelter, Stefan T, Fenner, Robert, Ford, Gary A, Gill, Aneet, Hunter, Rachael, James, Martin, Jayanthi, Archana, Lip, Gregory Y H, Massingham, Sue, Murray, Macey L, Mazurczak, Iwona, Nash, Philip S, Ndoutoumou, Amalia, Norrving, Bo, Sims, Hannah, Sprigg, Nikola, Vanniyasingam, Tishok, and Freemantle, Nick

Published
2024
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8. Polyp detection with colonoscopy assisted by the GI Genius artificial intelligence endoscopy module compared with standard colonoscopy in routine colonoscopy practice (COLO-DETECT): a multicentre, open-label, parallel-arm, pragmatic randomised controlled trial

Author

Cripps, Neil, Greenaway, John, Higham, Andrew, Jacob, John, Murugananthan, Aravinth, Nylander, David, Patel, Panna, Singh, Salil, Verma, Ajay M, Seager, Alexander, Sharp, Linda, Neilson, Laura J, Brand, Andrew, Hampton, James S, Lee, Tom J W, Evans, Rachel, Vale, Luke, Whelpton, John, Bestwick, Nathania, and Rees, Colin J

Published
2024
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11. Calibration and Cross-Validation of Accelerometry in Children and Adolescents with Cystic Fibrosis

Author

Bianchim, Mayara S., McNarry, Melitta A., Evans, Rachel, Thia, Lena, Barker, Alan R., Williams, Craig A., Denford, Sarah, and Mackintosh, Kelly A

Abstract

Commonly used cut-points may misclassify physical activity (PA) in people with cystic fibrosis (CF). The aim of this study was to develop and cross-validate condition-specific cut-points in children and adolescents with CF. Thirty-five children and adolescents with CF (15 girls; 11.6 ± 2.8 years) and 28 controls (16 girls; 12.2 ± 2.7 years), had their energy expenditure and triaxial acceleration measured during six daily activities of varying intensities. Euclidean Norm Minus One (ENMO) and Mean Amplitude Deviation (MAD) were extracted using both GENEActiv (both wrists) and ActiGraph GT9X (both wrists and right waist) accelerometers. ROC curves were used to determine healthy and CF-specific raw acceleration cut-points for sedentary time (SED), moderate physical activity (MPA) and vigorous physical activity (VPA). The PA cut-points were generally lower in CF compared to controls for both ENMO (60.2-73.1 vs. 63.5-86.8 mg) and MAD (58.9-85.2 vs. 75.9-93.7 mg). These substantial inter-cut-point differences support the need for disease-specific cut-points.

Published
2023
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13. Microbubble cavitation restores Staphylococcus aureus antibiotic susceptibility in vitro and in a septic arthritis model

Author

Zhao, Neil, Curry, Dylan, Evans, Rachel E., Isguven, Selin, Freeman, Theresa, Eisenbrey, John R., Forsberg, Flemming, Gilbertie, Jessica M., Boorman, Sophie, Hilliard, Rachel, Dastgheyb, Sana S., Machado, Priscilla, Stanczak, Maria, Harwood, Marc, Chen, Antonia F., Parvizi, Javad, Shapiro, Irving M., Hickok, Noreen J., and Schaer, Thomas P.

Published
2023
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16. Supermeres are functional extracellular nanoparticles replete with disease biomarkers and therapeutic targets

Author

Zhang, Qin, Jeppesen, Dennis K, Higginbotham, James N, Graves-Deal, Ramona, Trinh, Vincent Q, Ramirez, Marisol A, Sohn, Yoojin, Neininger, Abigail C, Taneja, Nilay, McKinley, Eliot T, Niitsu, Hiroaki, Cao, Zheng, Evans, Rachel, Glass, Sarah E, Ray, Kevin C, Fissell, William H, Hill, Salisha, Rose, Kristie Lindsey, Huh, Won Jae, Washington, Mary Kay, Ayers, Gregory Daniel, Burnette, Dylan T, Sharma, Shivani, Rome, Leonard H, Franklin, Jeffrey L, Lee, Youngmin A, Liu, Qi, and Coffey, Robert J

Subjects
Biochemistry and Cell Biology, Biological Sciences, Bioengineering, Rare Diseases, Nanotechnology, Orphan Drug, Alzheimer's Disease, Cancer, Acquired Cognitive Impairment, Dementia, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Brain Disorders, Development of treatments and therapeutic interventions, Aetiology, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Good Health and Well Being, Alzheimer Disease, Angiotensin-Converting Enzyme 2, Biological Transport, Biomarkers, COVID-19, Cardiovascular Diseases, Cell Communication, Cell Line, Tumor, Extracellular Vesicles, HeLa Cells, Humans, Lactic Acid, MicroRNAs, Nanoparticles, Neoplasms, Tumor Microenvironment, Hela Cells, Medical and Health Sciences, Developmental Biology, Biochemistry and cell biology
Abstract

Extracellular vesicles and exomere nanoparticles are under intense investigation as sources of clinically relevant cargo. Here we report the discovery of a distinct extracellular nanoparticle, termed supermere. Supermeres are morphologically distinct from exomeres and display a markedly greater uptake in vivo compared with small extracellular vesicles and exomeres. The protein and RNA composition of supermeres differs from small extracellular vesicles and exomeres. Supermeres are highly enriched with cargo involved in multiple cancers (glycolytic enzymes, TGFBI, miR-1246, MET, GPC1 and AGO2), Alzheimer's disease (APP) and cardiovascular disease (ACE2, ACE and PCSK9). The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab resistance and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential circulating biomarkers and therapeutic targets for a host of human diseases.

Published
2021

20. Person-Centered Palliative Care

Author

Spruijt, Odette, Manyari, Dante E., Halpin-Evans, Rachel, Glare, Paul, Mezzich, Juan E., editor, Appleyard, W. James, editor, Glare, Paul, editor, Snaedal, Jon, editor, and Wilson, C. Ruth, editor

Published
2023
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23. Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trial

Author

Marsden, John, Kelleher, Mike, Gilvarry, Eilish, Mitcheson, Luke, Bisla, Jatinder, Cape, Angela, Cowden, Fiona, Day, Edward, Dewhurst, Jonathan, Evans, Rachel, Hardy, Will, Hearn, Andrea, Kelly, Joanna, Lowry, Natalie, McCusker, Martin, Murphy, Caroline, Murray, Robert, Myton, Tracey, Quarshie, Sophie, Vanderwaal, Rob, Wareham, April, Hughes, Dyfrig, and Hoare, Zoë

Published
2023
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37. Safety behaviours in adolescent social anxiety

Author

Evans, Rachel and Clark, David Millar

Subjects
362.2
Abstract

Background: Social Anxiety Disorder (SoAD) in youth is often treated with a generic form of cognitive behavioural therapy (CBT). Some studies have suggested primary SoAD is associated with lower recovery rates following generic CBT compared to other anxiety disorders. Aims: This systematic review and meta-analysis investigated recovery rates following generic CBT for youth with primary SoAD versus other primary anxiety disorders. Method: 5 databases (Psycinfo, Web of Science, PubMed, Embase, Medline) were searched forrandomised controlled trials of generic CBT for child and/or adolescent anxiety. Results: 10 trials met criteria for inclusion in the systematic review, 6 of which presented sufficientdata for inclusion in the meta-analysis. 67 did not report data on recovery rates relative to primary diagnosis. The results of the systematic review were mixed. Across the trials included in the meta-analysis, the post-CBT recovery rate from primary SoAD (35%) was significantly lower than the recovery rate from other primary anxiety disorders (54%). Conclusions: Recovery from primary SoAD is significantly less likely than recovery from any other primary anxiety disorder following generic CBT in youth. This suggests a need for research to enhance the efficacy of CBT for youth SoAD.

Published
2020

38. The effect of manipulation of the phosphoinositide 3-kinase pathway on axon regeneration in vivo

Author

Evans, Rachel Shane and Martin, Keith R.

Subjects
617.7, axon regeneration, optic nerve crush, phosphoinositide 3-kinase pathway, retinal ganglion cell survival
Abstract

Millions worldwide are visually impaired by optic nerve diseases, and glaucoma, the leading cause of irreversible blindness, is due to affect approximately 80 million people by 2020. The optic nerve is comprised of retinal ganglion cell (RGC) axons, and like all mammalian central nervous system axons, they fail to regenerate due to a combination of extrinsic and intrinsic factors. Current treatments have limited success preventing disease progression, and this failed regeneration presents a major barrier to restoring vision. Previous research has demonstrated that manipulation of the phosphoinositide 3-kinase (PI3K) pathway by transgenic knockout of phosphatase and tensin homolog (PTEN) promotes survival and regeneration of murine RGC axons in an optic nerve crush (ONC) model. However, translation issues are yet to be addressed. PI3K converts phosphatidylinositol (3,4)-bis-phosphate (PIP2) lipids to phosphatidylinositol (3,4,5)-tris-phosphate (PIP3). PTEN acts as a pathway regulator, converting PIP3 back into PIP2. PIP3 is a second messenger molecule for several pathways, including the mammalian target of rapamycin (mTOR) pathway, which has been demonstrated to promote axon regeneration in RGCs, the spinal cord, and cortical neurons. The PI3K pathway is activated by growth factors, integrins and cytokine receptors. Integrins have also been shown to promote axon regeneration via the focal adhesion kinase pathway. This thesis aimed to determine the effects on axon regeneration of manipulating the PI3K pathway in various ways. A transgenic approach was adopted to conditionally express the hyperactive p110α and p110δ PI3K isoforms using viral Cre recombination. Both survival and axon regeneration were significantly increased 4 weeks post-ONC injury in young and aged mice. No significant difference between the two isoforms was observed, except that p110α promoted RGC survival in aged mice whereas p110δ had no significant effect. This was developed further using viral vectors to upregulate PI3K and to knockdown PTEN for a more translational approach: AAV2.shPTEN.GFP and AAV2.PI3K(p110δ). PTEN knockdown promoted both RGC survival and axon regeneration, while PI3K upregulation promoted axon regeneration. No significant difference in axon regeneration was seen between the two strategies. Where regeneration was seen, activation of the mTOR pathway was demonstrated. It is becoming increasingly clear that strategies need to be combined to achieve long-distance, robust regeneration. In this thesis, PI3K upregulation was combined with PTEN knockdown and then with integrin activation using AAV2.Integrin.V5 and AAV2.Kindlin.GFP viruses. While PI3K upregulation and PTEN knockdown promoted RGC survival and axon regeneration compared to control, this was not significantly more than PI3K upregulation alone. The experiments involving integrin activation were unsuccessful and the viruses need to be investigated further. While the field has achieved small numbers of regenerating axons up to the optic chiasm, key challenges for future work are reaching central targets in the brain and assessing axon regeneration in an aged model to better reflect the clinical setting, where neurodegenerative diseases predominately affect the aging population. In summary, the work in this thesis investigated the pro-regenerative effects of potential gene therapy targets, advancing our knowledge for developing future clinical strategies.

Published
2020
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45. Metformin and Inhibition of Transforming Growth Factor-Beta Stimulate In Vitro Transport in Primary Renal Tubule Cells

Author

Love, Harold, Evans, Rachel, Humes, Harvey David, Roy, Shuvo, Zent, Roy, Harris, Raymond, Wilson, Matthew, and Fissell, William Henry

Subjects
Engineering, Biomedical Engineering, Kidney Disease, Regenerative Medicine, Biotechnology, Bioengineering, Renal and urogenital, Cells, Cultured, Humans, Kidney Tubules, Metformin, Receptor, Transforming Growth Factor-beta Type I, Transforming Growth Factor beta, renal epithelial cells, NKCC2, TGF-beta, AMPK, metformin, Biochemistry and Cell Biology, Materials Engineering, Biomedical engineering
Abstract

Patient-oriented applications of cell culture include cell therapy of organ failure like chronic renal failure. Clinical deployment of a cell-based device for artificial renal replacement requires qualitative and quantitative fidelity of a cultured cell to its in vivo counterpart. Active specific apicobasal ion transport reabsorbs 90-99% of the filtered load of salt and water in the kidney. In a bioengineered kidney, tubular transport concentrates wastes and eliminates the need for hemodialysis, but renal tubule cells in culture transport little or no salt and water. We previously identified transforming growth factor-beta as a signaling pathway necessary for in vitro differentiation of renal tubule cells. Inhibition of TGF-β receptor-1 led to active inhabitable electrolyte and water transport by primary human renal tubule epithelial cells in vitro. Addition of metformin increased transport, in the context of a transient effect on 5' AMP-activated kinase phosphorylation. The signals that undermine in vitro differentiation are complex, but susceptible to pharmacologic intervention. This achievement overcomes a major hurdle limiting the development of a bioreactor of cultured cells for renal replacement therapy that encompasses not only endocrine and metabolic functions but also transport and excretion. Impact statement Clinical tissue engineering requires functional fidelity of the cultured cell to its in vivo counterpart, but this has been elusive in renal tissue engineering. Typically, renal tubule cells in culture have a flattened morphology and do not express key transporters essential to their function. In this study, we build on our prior work by using small molecules to modulate pathways affected by substrate elasticity. In doing so, we are able to enhance differentiation of these cells on conventional noncompliant substrates and show transport. These results are fundamentally enabling a new generation of cell-based renal therapies.

Published
2020

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