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592 results on '"WAGNER, JESSICA"'

52. Abstract 1778: B7-H3-CAR T-cell therapy in immune-competent osteosarcoma models: Regnase-1 KO overcomes limited CAR T-cell expansion

Author

Adeshakin, Adeleye O., primary, Zhou, Peipei, additional, Métais, Jean-Yves, additional, Nguyen, Phuong, additional, Perry, Scott, additional, Sheppard, Heather, additional, Sun, Xiang, additional, Cunningham, Trevor, additional, Shi, Hao, additional, Wagner, Jessica, additional, Yustein, Jason T., additional, DeRenzo, Christopher, additional, Krenciute, Giedre, additional, Chi, Hongbo, additional, and Gottschalk, Stephen, additional

Published
2023
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55. Supplemental Table 4 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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56. Supplemental Table 3 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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57. Supplemental Tables 5-7 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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58. Supplemental Table 1 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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60. Data from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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61. Supplementary Figures from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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62. Key Resources Table from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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63. Supplemental Table 8 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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64. Supplemental Table 2 from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, primary, Barbosa Vendramini-Costa, Débora, primary, Franco-Barraza, Janusz, primary, Wagner, Jessica, primary, Muir, Alexander, primary, Lau, Allison N., primary, Gabitova, Linara, primary, Pazina, Tatiana, primary, Gupta, Sapna, primary, Luong, Tiffany, primary, Rollins, Dustin, primary, Malik, Ruchi, primary, Thapa, Roshan J., primary, Restifo, Diana, primary, Zhou, Yan, primary, Cai, Kathy Q., primary, Hensley, Harvey H., primary, Tan, Yinfei, primary, Kruger, Warren D., primary, Devarajan, Karthik, primary, Balachandran, Siddharth, primary, Klein-Szanto, Andres J., primary, Wang, Huamin, primary, El-Deiry, Wafik S., primary, Vander Heiden, Matthew G., primary, Peri, Suraj, primary, Campbell, Kerry S., primary, Astsaturov, Igor, primary, and Cukierman, Edna, primary

Published
2023
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66. Correction: Desires for Individual- and Interpersonal-Level Patient Portal Use for HIV Prevention Among Urban Sexual Minority Men: Cross-sectional Study

Author

Jackman, Kevon-Mark P, primary, Tilchin, Carla, additional, Wagner, Jessica, additional, Flinn, Ryan E, additional, Trent, Maria, additional, Latkin, Carl, additional, Ruhs, Sebastian, additional, Fields, Errol L, additional, Hamill, Matthew M, additional, Mahaffey, Carlos, additional, Greenbaum, Adena, additional, and Jennings, Jacky M, additional

Published
2023
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68. Correction: Desires for Individual- and Interpersonal-Level Patient Portal Use for HIV Prevention Among Urban Sexual Minority Men: Cross-sectional Study (Preprint)

Author

Jackman, Kevon-Mark P, primary, Tilchin, Carla, additional, Wagner, Jessica, additional, Flinn, Ryan E, additional, Trent, Maria, additional, Latkin, Carl, additional, Ruhs, Sebastian, additional, Fields, Errol L, additional, Hamill, Matthew M, additional, Mahaffey, Carlos, additional, Greenbaum, Adena, additional, and Jennings, Jacky M, additional

Published
2023
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69. Desires for Individual- and Interpersonal-Level Patient Portal Use for HIV Prevention Among Urban Sexual Minority Men: Cross-sectional Study

Author

Jackman, Kevon-Mark P, primary, Tilchin, Carla, additional, Wagner, Jessica, additional, Flinn, Ryan E, additional, Trent, Maria, additional, Latkin, Carl, additional, Ruhs, Sebastian, additional, Fields, Errol L, additional, Hamill, Matthew M, additional, Mahaffey, Carlos, additional, Greenbaum, Adena, additional, and Jennings, Jacky M, additional

Published
2023
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76. The Role of Implied Motion in Engaging Audiences for Health Promotion: Encouraging Naps on a College Campus

Author

Mackert, Michael, Lazard, Allison, Guadagno, Marie, and Hughes Wagner, Jessica

Abstract

Objective: Lack of sleep among college students negatively impacts health and academic outcomes. Building on research that implied motion imagery increases brain activity, this project tested visual design strategies to increase viewers' engagement with a health communication campaign promoting napping to improve sleep habits. Participants: Participants (N = 194) were recruited from a large southwestern university in October 2012. Methods: Utilizing an experimental design, participants were assigned to 1 of 3 conditions: an implied motion superhero spokes-character, a static superhero spokes-character, and a control group. Results: The use of implied motion did not achieve the hypothesized effect on message elaboration, but superheroes are a promising persuasive tool for health promotion campaigns for college audiences. Conclusions: Implications for sleep health promotion campaigns and the role of implied motion in message design strategies are discussed, as well as future directions for research on the depiction of implied motion as it relates to theoretical development.

Published
2014
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78. Myocardial Injury and Altered Gene Expression Associated With SARS-CoV-2 Infection or mRNA Vaccination

Author

Altman, Natasha L., primary, Berning, Amber A., additional, Saxon, Cara E., additional, Adamek, Kylie E., additional, Wagner, Jessica A., additional, Slavov, Dobromir, additional, Quaife, Robert A., additional, Gill, Edward A., additional, Minobe, Wayne A., additional, Jonas, Eric R., additional, Carroll, Ian A., additional, Huebler, Sophia P., additional, Raines, Joshua, additional, Messenger, John C., additional, Ambardekar, Amrut V., additional, Mestroni, Luisa, additional, Rosenberg, Rachel M., additional, Rove, Jessica, additional, Campbell, Thomas B., additional, and Bristow, Michael R., additional

Published
2022
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83. Lipid Sorting by Ceramide Structure from Plasma Membrane to ER for the Cholera Toxin Receptor Ganglioside GM1

Author

Chinnapen, Daniel J.-F., Hsieh, Wan-Ting, te Welscher, Yvonne M., Saslowsky, David E., Kaoutzani, Lydia, Brandsma, Eelke, D'Auria, Ludovic, Park, Hyejung, Wagner, Jessica S., Drake, Kimberly R., Kang, Minchul, Benjamin, Thomas, Ullman, M. David, Costello, Catherine E., Kenworthy, Anne K., Baumgart, Tobias, Massol, Ramiro H., and Lencer, Wayne I.

Published
2012
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84. Enacted Sexual Minority Stigma, Psychological Distress, and Sexual and Drug Risk Behaviors Among Urban Men Who Have Sex with Men (MSM)

Author

Silvestri, Francesca, primary, Tilchin, Carla, additional, Wagner, Jessica, additional, Hamill, Matthew M., additional, Rompalo, Anne, additional, Ghanem, Khalil G., additional, Schumacher, Christina, additional, Ruhs, Sebastian, additional, Greenbaum, Adena, additional, Latkin, Carl, additional, and Jennings, Jacky M., additional

Published
2022
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87. Pre-post Evaluation of the "Supporting Student-Athlete Mental Wellness" Module for College Coaches.

Author

Kroshus, Emily, Wagner, Jessica, Wyrick, David L., and Hainline, Brian

Subjects
COLLEGE athletes, MENTAL health, COACHES (Athletics), HEALTH literacy, SPORTS teams
Abstract

This study sought to determine whether completion of the National Collegiate Athletic Association's "Supporting Student-Athlete Mental Wellness" online module for coaches increased mental health literacy, reduced stigma, and increased intentions to: 1) communicate proactively with team members about the importance of mental health care seeking, and 2) respond appropriately to support an athlete believed to be struggling with a mental health issue. College head coaches completed pre-test surveys (n = 969) and immediate post-test surveys (n = 347, completion rate = 36%). Module completion was associated with increased mental health literacy, decreased stigma about help seeking and increased intentions to engage in culture setting communication. These findings suggest that the online module is a good start for coach education about mental health; however, additional modifications may be warranted to the extent coach referral to sports medicine staff or provision of emotional support to student-athletes struggling with mental health concerns are considered desired behaviors. [ABSTRACT FROM AUTHOR]

Published
2019
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88. Medin co-aggregates with vascular amyloid-beta in Alzheimers disease

Author

Wagner, Jessica, Degenhardt, Karoline, Veit, Marleen, Louros, Nikolaos, Konstantoulea, Katerina, Skodras, Angelos, Wild, Katleen, Liu, Ping, Obermueller, Ulrike, Bansal, Vikas, Dalmia, Anupriya, Haesler, Lisa M., Lambert, Marius, De Vleeschouwer, Matthias, Davies, Hannah A., Madine, Jillian, Kronenberg-Versteeg, Deborah, Feederle, Regina, Del Turco, Domenico, Nilsson, Peter, Lashley, Tammaryn, Deller, Thomas, Gearing, Marla, Walker, Lary C., Heutink, Peter, Rousseau, Frederic, Schymkowitz, Joost, Jucker, Mathias, Neher, Jonas J., Wagner, Jessica, Degenhardt, Karoline, Veit, Marleen, Louros, Nikolaos, Konstantoulea, Katerina, Skodras, Angelos, Wild, Katleen, Liu, Ping, Obermueller, Ulrike, Bansal, Vikas, Dalmia, Anupriya, Haesler, Lisa M., Lambert, Marius, De Vleeschouwer, Matthias, Davies, Hannah A., Madine, Jillian, Kronenberg-Versteeg, Deborah, Feederle, Regina, Del Turco, Domenico, Nilsson, Peter, Lashley, Tammaryn, Deller, Thomas, Gearing, Marla, Walker, Lary C., Heutink, Peter, Rousseau, Frederic, Schymkowitz, Joost, Jucker, Mathias, and Neher, Jonas J.

Abstract

Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age(1,)(2), making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction(3). Here we demonstrate in amyloid-beta precursor protein (APP) transgenic mice and in patients with Alzheimers disease that medin co-localizes with vascular amyloid-beta deposits, and that in mice, medin deficiency reduces vascular amyloid-beta deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-beta burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimers disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-beta to promote its aggregation, as medin forms heterologous fibrils with amyloid-beta, affects amyloid-beta fibril structure, and cross-seeds amyloid-beta aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-beta deposition in the blood vessels of the brain., Funding Agencies|Deutsche Forschungsgemeinschaft (DFG) [NE 1951/2-1, NE 1951/2-2, JU655/4-1]; EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking (IMPRiND grant) [116060]; Hans und Ilse Breuer-Stiftung; China Scholarship Council; FEBS short term travel fellowship; British Heart Foundation Intermediate Basic Science fellowship [FS/12/61/29877]; Swedish Research Council; Flanders Institute for Biotechnology (VIB) [C0401]; Fund for Scientific Research Flanders (FWO) [G0C3522N, 12P0919N, 12P0922N]; Stichting Alzheimer Onderzoek/Fondation Recherche Alzheimer [SAO-FRA 2020/0013]; Alzheimers Research UK senior fellowship; Alexander von Humboldt Foundation research fellowship; NIA [P30AG10161, R01AG15819, R01AG17917, U01AG46152, U01AG61356, P50AG025688]; Illinois Department of Public Health (ROSMAP); Translational Genomics Research Institute

Published
2022
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89. Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

Author

Francescone, Ralph, Barbosa Vendramini-Costa, Débora, Franco-Barraza, Janusz, Wagner, Jessica, Muir, Alexander, Lau, Allison N., Gabitova, Linara, Pazina, Tatiana, Gupta, Sapna, Luong, Tiffany, Rollins, Dustin, Malik, Ruchi, Thapa, Roshan J., Restifo, Diana, Zhou, Yan, Cai, Kathy Q., Hensley, Harvey H., Tan, Yinfei, Kruger, Warren D., Devarajan, Karthik, Balachandran, Siddharth, Klein-Szanto, Andres J., Wang, Huamin, El-Deiry, Wafik S., Vander Heiden, Matthew G., Peri, Suraj, Campbell, Kerry S., Astsaturov, Igor, Cukierman, Edna, Francescone, Ralph, Barbosa Vendramini-Costa, Débora, Franco-Barraza, Janusz, Wagner, Jessica, Muir, Alexander, Lau, Allison N., Gabitova, Linara, Pazina, Tatiana, Gupta, Sapna, Luong, Tiffany, Rollins, Dustin, Malik, Ruchi, Thapa, Roshan J., Restifo, Diana, Zhou, Yan, Cai, Kathy Q., Hensley, Harvey H., Tan, Yinfei, Kruger, Warren D., Devarajan, Karthik, Balachandran, Siddharth, Klein-Szanto, Andres J., Wang, Huamin, El-Deiry, Wafik S., Vander Heiden, Matthew G., Peri, Suraj, Campbell, Kerry S., Astsaturov, Igor, and Cukierman, Edna

Abstract

© 2020 American Association for Cancer Research. Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1+ cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosup-pressive and inhibit natural killer cell–mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutral-izing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC. SIGNIFICANCE: This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis in vivo by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function.

Published
2022

91. 2. Diagnose der FASD

Author

Landgraf, Mirjam N., primary, Becker, Gela, additional, Wagner, Jessica C., additional, and Hennicke, Klaus, additional

Published
2015
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93. Sexually Transmitted Infection Transmission Dynamics During the Coronavirus Disease 2019 (COVID-19) Pandemic Among Urban Gay, Bisexual, and Other Men Who Have Sex With Men

Author

Schumacher, Christina M, primary, Thornton, Nicole, additional, Wagner, Jessica, additional, Tilchin, Carla, additional, Ghanem, Khalil G, additional, Hamill, Matthew M, additional, Latkin, Carl, additional, Rompalo, Anne, additional, Ruhs, Sebastian, additional, Greenbaum, Adena, additional, and Jennings, Jacky M, additional

Published
2022
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97. Myocardial Injury and Altered Gene Expression Associated with SARS-CoV-2 Infection or mRNA Vaccination

Author

Altman, Natasha Lipson, primary, Berning, Amber, additional, Saxon, Cara E., additional, Adamek, Kylie E., additional, Wagner, Jessica A., additional, Slavov, Dobromir, additional, Quaife, Robert A., additional, Gill, Edward A., additional, Minobe, Wayne A., additional, Jonas, Eric R., additional, Carroll, Ian, additional, Huebler, Sophia P., additional, Raines, Joshua, additional, Messenger, John, additional, Ambardekar, Amrut Vijay, additional, Mestroni, Luisa, additional, Rosenberg, Rachel M., additional, Rove, Jessica Y., additional, Campbell, Thomas, additional, and Bristow, Michael R., additional

Published
2022
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98. The role of Medin, the most common human amyloid, in cerebrovascular disease and cerebral β-amyloidosis

Author

Wagner, Jessica and Neher, Jonas (Dr.)

Subjects
Alzheimerkrankheit , Neurowissenschaften , Blutgefäß , Amyloid
Abstract

Amyloids occur as localized or systemic deposits composed of compact β-sheet fibrils of abnormally folded proteins that may disrupt the physiological function of the afflicted tissue by loss-of-function or gain-of-toxicity. The best characterized amyloid, amyloid-β (Aβ) is a known trigger of the molecular and cellular cascade leading to Alzheimer’s disease (AD). Aβ aggregation can amplify via a prion-like seeding mechanism and rapidly spread in the brain connectome. Several downstream processes potentiate the toxic cascade, ultimately resulting in brain damage and memory loss. Interestingly, vascular dysfunction is described as an early symptom of AD in humans. Recently, a study identified another protein that deposits in the vasculature of the AD brain – Medin amyloid (an internal fragment of MFG-E8). Medin is the most common human vascular amyloid known to date, as it can be detected within the thoracic aorta and the upper body arteries of nearly everyone above 50 years of age. As the name Medin suggests, it predominantly deposits along the elastic fibers of the tunica media. Because of its vascular localization and potential role in arterial aging it has been suggested as a possible risk factor of AD. However, despite its high prevalence in the aging population, no causal role in human pathogenesis was previously reported. Nevertheless, in vitro studies have described common structural, physicochemical and cytotoxic amyloid properties for Medin, and analyses of human tissue derived from autopsy or surgery implicate a role for Medin in vascular diseases. However, the question of a mechanistic link between the presence of Medin, cerebrovascular dysfunction and AD pathology remains elusive due to lack of appropriate experimental in vivo models, which would enable mechanistic studies. In this dissertation, a suitable animal model to investigate the influence of Medin aggregates on cerebrovascular function was established. In particular, we found that with advancing age wild-type mice develop endogenous Medin aggregates in the aorta and cerebral arteries that resemble the sequence, biochemical properties, and morphology of human Medin amyloid. We also showed in our first study that age-associated decline in cerebral vascular function (evident by impaired artery elasticity) in living mice was rescued by prevention of vascular Medin aggregate formation through a genetic knockout of the Medin-containing C2 domain of MFG-E8 (Mfge8 C2 KO). These observations implicate Medin as a causal factor in age-associated cerebrovascular dysfunction for the first time. Given the fact that Medin was recently shown to template aggregation of serum amyloid A, our second study addressed whether potential co-aggregation of Medin and Aβ may exacerbate AD pathology. Indeed, our study provided first evidence for a direct amyloid-amyloid interaction of Medin and Aβ in two mouse models for cerebral β-amyloidosis. Medin did not only co-localize substantially with Aβ deposits in the brain, but the genetic deletion of Medin also altered plaque and fibril structure in vitro and in vivo, prevented MFG-E8/Medin accumulation within plaques and vasculature, and slowed the onset of pathology in cerebral β-amyloidosis. It is further important to note that in line with its vascular localization in humans, genetic Medin deficiency reduced cerebral β-amyloid angiopathy (CAA) and related microhemorrhages even at end-stage amyloid pathology. Additionally, aorta-derived Medin 'seeds' promoted pre-mature Aβ aggregation in the brain, suggesting that Medin promotes Aβ by a heterologous seeding mechanism. To analyze the translational relevance of a potential heterologous seeding mechanism between Medin and Aβ, we also examined data from the dorsolateral prefrontal cortex of >500 patients from the ROS/MAP cohorts, two longitudinal clinical studies on aging, cognitive decline and AD. Importantly, AD patients showed significantly increased MFGE8 expression compared to non-demented patients. Moreover, MFGE8 gene expression levels predicted cognitive decline independent of amyloid neuropathology, namely Aβ plaques and neurofibrillary tangles. Notably, Medin was previously reported to be increased within cerebral arteries of AD patients in comparison to non-demented controls, and levels of arteriole Medin predicted risk for AD independent of amyloid pathology, age, sex and ApoE status. In summary, this thesis demonstrates the importance to develop new technologies and models to study amyloid pathobiology and cross-talk, as amyloids contribute to common age-related damage and dysfunction, but also affect progression, heterogeneity and co-morbidity of other diseases. Our studies demonstrate a new mechanism that may drive age-associated vascular disease and cerebral β-amyloid angiopathy, highlighting Medin as a potential therapeutic target to maintain vascular health and cognitive function with age.

Published
2021

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