HIV, HCV, Hippo, and Liver Disease Progression

HIV、HCV、Hippo 和肝病进展

• 批准号: 10303053
• 负责人: RAYMOND T CHUNG
• 金额: $ 63.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-03 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303053
• 关键词: Address; Affect; Animal Model; Antiviral Therapy; Apoptosis; Attenuated; Binding; Cause of Death; Cell Aging; Cell Culture Techniques; Cell Nucleus; Cell Proliferation; Cicatrix; Cirrhosis; Cues; Cytoplasm; Development; Disease Progression; Drug Targeting; EGF gene; Embryo; Environment; Etiology; Exposure to; Extracellular Matrix; Fibrosis; Foundations; Gene Expression; HIV; HIV Infections; HIV Seropositivity; HIV/HCV; Health; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatitis C; Hepatitis C Therapy; Hepatitis C co-infection; Hepatitis C virus; Hepatocyte; Human; In Vitro; Individual; Interruption; Liver; Liver Fibrosis; Liver diseases; Lung; Mechanoreceptors; Mediating; Modeling; Morbidity - disease rate; Mus; Myofibroblast; Nuclear; Nuclear Translocation; Organ; Pathogenesis; Pathway interactions; Persons; Play; Process; Proteins; Reactive Oxygen Species; Role; Signal Pathway; Signal Transduction; Smad Proteins; Transcriptional Activation; Transforming Growth Factor beta; Validation; Verteporfin; Work; antifibrotic treatment; antiretroviral therapy; co-infection; defined contribution; density; end stage liver disease; fibrogenesis; human embryonic stem cell; human model; in vivo; inhibitor; kidney fibrosis; liver injury; mortality; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; programs; stem; transmission process

Coinfection with HCV occurs in approximately 30% of HIV-positive persons. It has been well recognized that HIV infection accelerates liver fibrosis progression in the setting of HCV coinfection, although the precise mechanisms underlying this have not been fully elucidated. While great advances have been made in direct acting antiviral (DAA) therapy for HCV, HIV infection alone has increasingly been recognized as a cause of liver fibrosis. Liver disease remains the second most common cause of death in HIV-positive individuals in the active ART era. In addition, progressive hepatic fibrosis is often not recognized until cirrhosis and/or sequelae from its complications have supervened, long after DAAs can reverse the findings. This reality is further compounded by the lack of therapies that halt fibrosis progression. Uncovering the mechanisms underlying fibrosis progression and identifying new targets in HIV infected persons are therefore a high priority. YAP/TAZ are critical intermediates in the Hippo signaling pathway that regulate cell proliferation. In the Hippo “on” state, YAP/TAZ are phosphorylated in the cytoplasm, leading to inactivation of YAP/TAZ and cell senescence or apoptosis. In the Hippo “off” state, YAP/TAZ translocates to the nucleus and regulates cell proliferation and fibrogenesis. In addition, YAP/TAZ also respond to extracellular matrix (ECM) cues by sensing the density of the ECM to further augment fibrogenesis. Thus, YAP/TAZ nuclear localization has been induced by stiffer ECM, leading to hepatic stellate cell (HSC) activation and fibrogenesis, further aggravating fibrosis. In earlier work, we demonstrated that HIV accentuates an HCV-driven profibrogenic program, mediated through reactive oxygen species, NF-κB and TGFβ1, in both hepatocytes and HSCs. The YAP/TAZ pathway also converges with the TGFβ1 pathway, as YAP/TAZ can also act as mechanoreceptors that regulate TGFβ1 signaling via direct binding of YAP/TAZ to SMAD proteins, as a function of the stiffness of the ECM in human embryonic stem cells. The importance of the TGFβ1 pathway in fibrosis progression in HIV/HCV coinfection suggests that YAP/TAZ plays a critical role in mediating liver disease progression in HIV. To this end, we have demonstrated that HIV can induce YAP/TAZ-regulated profibrogenic gene expression in HSCs, and HCV can do the same in hepatocytes. In addition, several targets upstream of YAP/TAZ are known to bind to HIV and its proteins, further implicating YAP/TAZ in liver disease pathogenesis in HIV. However, detailed studies regarding these associations are lacking. Given the overlap of YAP/TAZ with TGFβ1, the mechanoregulatory function of YAP/TAZ, the importance of TGFβ1 in HIV-related liver fibrosis, and the known upstream targets of YAP/TAZ that interact with HIV, we hypothesize that YAP/TAZ is pivotal to the pathogenesis of HIV-related liver fibrosis. We will address these relationships through the following Specific Aims: (1) define the contribution of YAP/TAZ pathway activation to hepatic fibrogenesis in the context of HCV and other liver diseases; (2) determine the mechanism(s) by which HIV induces YAP/TAZ activation with/without HCV; and (3) define the contribution of the extracellular matrix to HIV-mediated YAP/TAZ activation. By clarifying the relationship between HIV, HCV, YAP/TAZ, and TGFβ, the studies in this proposal are likely to uncover new targets for antifibrotic agents.

约30%的HIV阳性者同时感染HCV。众所周知，艾滋病毒感染 在HCV合并感染的情况下加速肝纤维化进展，尽管其确切机制尚不清楚， 还没有完全阐明。虽然在HCV的直接作用抗病毒（DAA）治疗方面已经取得了很大进展， 艾滋病毒感染已越来越多地被认为是肝纤维化的原因。肝病仍然是第二大 在活跃的抗逆转录病毒疗法时代，艾滋病毒阳性个体的常见死亡原因。此外，进行性肝纤维化通常 直到肝硬化和/或其并发症的后遗症发生时才被认识到，在DAA可以逆转 调查结果。由于缺乏阻止纤维化进展的疗法，这一现实进一步加剧。揭开 因此，在HIV感染者中识别纤维化进展的潜在机制和新靶点是一个高风险的研究。 要务雅普/TAZ是Hippo信号通路中调节细胞增殖的关键中间体。在河马 “开启”状态下，雅普/TAZ在细胞质中被磷酸化，导致雅普/TAZ失活和细胞衰老，或 凋亡在Hippo“关闭”状态下，雅普/TAZ易位至细胞核并调节细胞增殖和纤维化。 此外，雅普/TAZ还通过感测细胞外基质（ECM）的密度来响应ECM信号，以进一步促进细胞外基质（ECM）的表达。 增加纤维形成。因此，雅普/TAZ核定位已被较硬的ECM诱导，导致肝星状细胞凋亡。 细胞（HSC）活化和纤维形成，进一步加重纤维化。 在早期的工作中，我们证明了艾滋病毒加重了丙型肝炎病毒驱动的促纤维化程序，通过反应性介导， 在肝细胞和HSC中的氧种类、NF-κB和TGFβ1。雅普/TAZ途径也与 TGFβ1通路，如雅普/TAZ也可以作为机械受体，通过直接结合 雅普/TAZ与SMAD蛋白的关系，作为人胚胎干细胞中ECM硬度的函数。的重要性 TGFβ1通路在HIV/HCV合并感染的纤维化进展中表明，雅普/TAZ在 介导HIV的肝脏疾病进展。为此，我们已经证明，HIV可以诱导雅普/TAZ调节的 在HSC中的促纤维化基因表达，并且HCV可以在肝细胞中做同样的事情。此外，上游的几个目标 已知的雅普/TAZ与HIV及其蛋白质结合，进一步暗示雅普/TAZ在HIV的肝病发病机制中。 然而，缺乏关于这些关联的详细研究。考虑到雅普/TAZ与TGFβ1的重叠， 雅普/TAZ的机械调节功能，TGFβ1在HIV相关肝纤维化中的重要性，以及已知的肝纤维化的上游调控机制。 由于雅普/TAZ的靶点与HIV相互作用，我们推测雅普/TAZ在HIV相关性肝脏的发病机制中起关键作用 纤维化我们将通过以下具体目标来处理这些关系：（1）确定雅普/TAZ的贡献 在HCV和其他肝脏疾病的背景下，肝纤维化的途径激活;（2）确定机制 HIV诱导雅普/TAZ活化的机制;以及（3）确定细胞外基质对 HIV介导的雅普/TAZ激活。通过阐明HIV、HCV、雅普/TAZ和TGFβ之间的关系， 这一建议可能会发现抗纤维化药物的新靶点。

项目成果

Clonal haematopoiesis and risk of chronic liver disease.

• DOI: 10.1038/s41586-023-05857-4
• 发表时间: 2023-04
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Wong, Waihay J.;Emdin, Connor;Bick, Alexander G.;Zekavat, Seyedeh M.;Niroula, Abhishek;Pirruccello, James P.;Dichtel, Laura;Griffin, Gabriel;Uddin, Md Mesbah;Gibson, Christopher J.;Kovalcik, Veronica;Lin, Amy E.;McConkey, Marie E.;Vromman, Amelie;Sellar, Rob S.;Kim, Peter G.;Agrawal, Mridul;Weinstock, Joshua;Long, Michelle T.;Yu, Bing;Banerjee, Rajarshi;Nicholls, Rowan C.;Dennis, Andrea;Kelly, Matt;Loh, Po-Ru;McCarroll, Steve;Boerwinkle, Eric;Vasan, Ramachandran S.;Jaiswal, Siddhartha;Johnson, Andrew D.;Chung, Raymond T.;Corey, Kathleen;Levy, Daniel;Ballantyne, Christie;Ebert, Benjamin L.;Natarajan, Pradeep;Abe, Namiko;Abecasis, Goncalo;Aguet, Francois;Albert, Christine;Almasy, Laura;Alonso, Alvaro;Ament, Seth;Anderson, Peter;Anugu, Pramod;Applebaum-Bowden, Deborah;Ardlie, Kristin;Arking, Dan;Arnett, Donna K.;Ashley-Koch, Allison;Aslibekyan, Stella;Assimes, Tim;Auer, Paul;Avramopoulos, Dimitrios;Ayas, Najib;Balasubramanian, Adithya;Barnard, John;Barnes, Kathleen;Barr, R. Graham;Barron-Casella, Emily;Barwick, Lucas;Beaty, Terri;Beck, Gerald;Becker, Diane;Becker, Lewis;Beer, Rebecca;Beitelshees, Amber;Benjamin, Emelia;Benos, Takis;Bezerra, Marcos;Bielak, Larry;Bis, Joshua;Blackwell, Thomas;Blangero, John;Blue, Nathan;Bowden, Donald W.;Bowler, Russell;Brody, Jennifer;Broeckel, Ulrich;Broome, Jai;Brown, Deborah;Bunting, Karen;Burchard, Esteban;Bustamante, Carlos;Buth, Erin;Cade, Brian;Cardwell, Jonathan;Carey, Vincent;Carrier, Julie;Carson, April P.;Carty, Cara;Casaburi, Richard;Casas Romero, Juan P.;Casella, James;Castaldi, Peter;Chaffin, Mark;Chang, Christy;Chang, Yi-Cheng;Chasman, Daniel;Chavan, Sameer;Chen, Bo-Juen;Chen, Wei-Min;Chen, Yii-Der Ida;Cho, Michael;Choi, Seung Hoan;Chuang, Lee-Ming;Chung, Mina;Chung, Ren-Hua;Clish, Clary;Comhair, Suzy;Conomos, Matthew;Cornell, Elaine;Correa, Adolfo;Crandall, Carolyn;Crapo, James;Cupples, L. Adrienne;Curran, Joanne;Curtis, Jeffrey;Custer, Brian;Damcott, Coleen;Darbar, Dawood;David, Sean;Davis, Colleen;Daya, Michelle;de Andrade, Mariza;de las Fuentes, Lisa;de Vries, Paul;DeBaun, Michael;Deka, Ranjan;DeMeo, Dawn;Devine, Scott;Dinh, Huyen;Doddapaneni, Harsha;Duan, Qing;Dugan-Perez, Shannon;Duggirala, Ravi;Durda, Jon Peter;Dutcher, Susan K.;Eaton, Charles;Ekunwe, Lynette;El Boueiz, Adel;Ellinor, Patrick;Emery, Leslie;Erzurum, Serpil;Farber, Charles;Farek, Jesse;Fingerlin, Tasha;Flickinger, Matthew;Fornage, Myriam;Franceschini, Nora;Frazar, Chris;Fu, Mao;Fullerton, Stephanie M.;Fulton, Lucinda;Gabriel, Stacey;Gan, Weiniu;Gao, Shanshan;Gao, Yan;Gass, Margery;Geiger, Heather;Gelb, Bruce;Geraci, Mark;Germer, Soren;Gerszten, Robert;Ghosh, Auyon;Gibbs, Richard;Gignoux, Chris;Gladwin, Mark;Glahn, David;Gogarten, Stephanie;Gong, Da-Wei;Goring, Harald;Graw, Sharon;Gray, Kathryn J.;Grine, Daniel;Gross, Colin;Gu, C. Charles;Guan, Yue;Guo, Xiuqing;Gupta, Namrata;Haessler, Jeff;Hall, Michael;Han, Yi;Hanly, Patrick;Harris, Daniel;Hawley, Nicola L.;He, Jiang;Heavner, Ben;Heckbert, Susan;Hernandez, Ryan;Herrington, David;Hersh, Craig;Hidalgo, Bertha;Hixson, James;Hobbs, Brian;Hokanson, John;Hong, Elliott;Hoth, Karin;Hsiung, Chao (Agnes);Hu, Jianhong;Hung, Yi-Jen;Huston, Haley;Hwu, Chii Min;Irvin, Marguerite Ryan;Jackson, Rebecca;Jain, Deepti;Jaquish, Cashell;Johnsen, Jill;Johnson, Craig;Johnston, Rich;Jones, Kimberly;Kang, Hyun Min;Kaplan, Robert;Kardia, Sharon;Kelly, Shannon;Kenny, Eimear;Kessler, Michael;Khan, Alyna;Khan, Ziad;Kim, Wonji;Kimoff, John;Kinney, Greg;Konkle, Barbara;Kooperberg, Charles;Kramer, Holly;Lange, Christoph;Lange, Ethan;Lange, Leslie;Laurie, Cathy;Laurie, Cecelia;LeBoff, Meryl;Lee, Jiwon;Lee, Sandra;Lee, Wen-Jane;LeFaive, Jonathon;Levine, David;Lewis, Joshua;Li, Xiaohui;Li, Yun;Lin, Henry;Lin, Honghuang;Lin, Xihong;Liu, Simin;Liu, Yongmei;Liu, Yu;Loos, Ruth J. F.;Lubitz, Steven;Lunetta, Kathryn;Luo, James;Magalang, Ulysses;Mahaney, Michael;Make, Barry;Manichaikul, Ani;Manning, Alisa;Manson, JoAnn;Martin, Lisa;Marton, Melissa;Mathai, Susan;Mathias, Rasika;May, Susanne;McArdle, Patrick;McDonald, Merry-Lynn;McFarland, Sean;McGarvey, Stephen;McGoldrick, Daniel;McHugh, Caitlin;McNeil, Becky;Mei, Hao;Meigs, James;Menon, Vipin;Mestroni, Luisa;Metcalf, Ginger;Meyers, Deborah A.;Mignot, Emmanuel;Mikulla, Julie;Min, Nancy;Minear, Mollie;Minster, Ryan L.;Mitchell, Braxton D.;Moll, Matt;Momin, Zeineen;Montasser, May E.;Montgomery, Courtney;Muzny, Donna;Mychaleckyj, Josyf C.;Nadkarni, Girish;Naik, Rakhi;Naseri, Take;Nekhai, Sergei;Nelson, Sarah C.;Neltner, Bonnie;Nessner, Caitlin;Nickerson, Deborah;Nkechinyere, Osuji;North, Kari;O'Connell, Jeff;O'Connor, Tim;Ochs-Balcom, Heather;Okwuonu, Geoffrey;Pack, Allan;Paik, David T.;Palmer, Nicholette;Pankow, James;Papanicolaou, George;Parker, Cora;Peloso, Gina;Peralta, Juan Manuel;Perez, Marco;Perry, James;Peters, Ulrike;Peyser, Patricia;Phillips, Lawrence S.;Pleiness, Jacob;Pollin, Toni;Post, Wendy;Powers Becker, Julia;Preethi Boorgula, Meher;Preuss, Michael;Psaty, Bruce;Qasba, Pankaj;Qiao, Dandi;Qin, Zhaohui;Rafaels, Nicholas;Raffield, Laura;Rajendran, Mahitha;Rao, D. C.;Rasmussen-Torvik, Laura;Ratan, Aakrosh;Redline, Susan;Reed, Robert;Reeves, Catherine;Regan, Elizabeth;Reiner, Alex;Reupena, Muagututi'a Sefuiva;Rice, Ken;Rich, Stephen;Robillard, Rebecca;Robine, Nicolas;Roden, Dan;Roselli, Carolina;Rotter, Jerome;Ruczinski, Ingo;Runnels, Alexi;Russell, Pamela;Ruuska, Sarah;Ryan, Kathleen;Sabino, Ester Cerdeira;Saleheen, Danish;Salimi, Shabnam;Salvi, Sejal;Salzberg, Steven;Sandow, Kevin;Sankaran, Vijay G.;Santibanez, Jireh;Schwander, Karen;Schwartz, David;Sciurba, Frank;Seidman, Christine;Seidman, Jonathan;Series, Frederic;Sheehan, Vivien;Sherman, Stephanie L.;Shetty, Amol;Shetty, Aniket;Sheu, Wayne Hui-Heng;Shoemaker, M. 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Keoki;Williams, Scott;Wilson, Carla;Wilson, James;Winterkorn, Lara;Wong, Quenna;Wu, Joseph;Xu, Huichun;Yanek, Lisa;Yang, Ivana;Yu, Ketian;Zhang, Yingze;Zhao, Snow Xueyan;Zhao, Wei;Zhu, Xiaofeng;Ziv, Elad;Zody, Michael;Zoellner, Sebastian
• 通讯作者: Zoellner, Sebastian

Insights Into the Pathophysiology of Liver Disease in HCV/HIV: Does it End With HCV Cure?

深入了解 HCV/HIV 肝病的病理生理学：HCV 治愈会结束吗？

• DOI: 10.1093/infdis/jiaa279
• 发表时间: 2020
• 期刊: The Journal of infectious diseases
• 作者: Jeyarajan,AndreJ;Chung,RaymondT
• 通讯作者: Chung,RaymondT

Fatty Acids Activate the Transcriptional Coactivator YAP1 to Promote Liver Fibrosis via p38 Mitogen-Activated Protein Kinase.

• DOI: 10.1016/j.jcmgh.2021.06.003
• 发表时间: 2021
• 期刊: Cellular and molecular gastroenterology and hepatology
• 影响因子: 7.2
• 作者: Salloum S;Jeyarajan AJ;Kruger AJ;Holmes JA;Shao T;Sojoodi M;Kim MH;Zhuo Z;Shroff SG;Kassa A;Corey KE;Khan SK;Lin W;Alatrakchi N;Schaefer EAK;Chung RT
• 通讯作者: Chung RT

Peroxidasin Deficiency Re-programs Macrophages Toward Pro-fibrolysis Function and Promotes Collagen Resolution in Liver.

• DOI: 10.1016/j.jcmgh.2022.01.015
• 发表时间: 2022
• 期刊: CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
• 影响因子: 7.2
• 作者: Sojoodi, Mozhdeh;Erstad, Derek J.;Barrett, Stephen C.;Salloum, Shadi;Zhu, Shijia;Qian, Tongqi;Colon, Selene;Gale, Eric M.;Jordan, Veronica Clavijo;Wang, Yongtao;Li, Shen;Ataeinia, Bahar;Jalilifiroozinezhad, Sasan;Lanuti, Michael;Zukerberg, Lawrence;Caravan, Peter;Hoshida, Yujin;Chung, Raymond T.;Bhave, Gautam;Lauer, Georg M.;Fuchs, Bryan C.;Tanabe, Kenneth K.
• 通讯作者: Tanabe, Kenneth K.