Primary amyloidosis (AL), the most common systemic amyloidosis in the US, is a plasma cell dyscrasia resulting in the clonal production of immunoglobulin light chain proteins and subsequent amyloid fibril deposition in multi-organ, The heart and the kidney, alone or together, are the most frequently involved organs. Cardiac involvement with congestive heart failure is the most frequent cause of death in primary amyloidosis, due to the development of a rapidly progressive cardiomyopathy, with ill prognosis, usually within months. While this disease has been identified decades ago, yet, the molecular mechanisms underlying primary amyloid cardiomyopathy remain unknown. We have recently provided the first insights into the pathophysiology of primary amyloid cardiomyopathy, challenging existing hypotheses - that cardiac dysfunction is secondary to physical infiltration of the myocardium by amyloid fibrils and demonstrating, for the first time, a direct effect of human amyloidogenic light chain proteins on cardiomyocyte function independent of amyloid fibril formation. Furthermore, our data suggest that amyloid light chain proteins induced cardiomyocyte dysfunction is through activation of specific cellular signaling pathways and generation of reactive oxygen species. These findings have provided the first mechanistic insight into primary amyloid cardiomyopathy, and have led to the generation of our central hypothesis that circulating immunoglobulin light chains directly result in cardiomyocyte dysfunction and contribute to the rapid progression of primary amyloid cardiomyopathy, independent of interstitial fibril deposition, through activation of redox-sensitive and stress-activated kinases signaling cascades, and subsequent cellular oxidant stress. Utilizing a multidisciplinary approach of cellular biology, cardiomyocyte physiology, and genetics, as well as in-vitro and in-vivo methodologies, the major goal of this proposal is to expand upon our previous findings and to determine specifically: (1) the molecular mechanisms underlying primary amyloid cardiomyopathy (Specific Aims 1 &2) and (2) potential therapeutic targets for the treatment of primary amyloid cardiomyopathy (Specific Aim 3). The results obtained from this proposal, we hope to contribute to our understanding of AL cardiomyopathy, and thus, harness the therapeutic potential to cure this rapidly fatal disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088533-04
Application #
7807170
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Przywara, Dennis
Project Start
2007-07-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$430,000
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Sapp, Valerie; Jain, Mohit; Liao, Ronglih (2016) Viewing Extrinsic Proteotoxic Stress Through the Lens of Amyloid Cardiomyopathy. Physiology (Bethesda) 31:294-9
Kuster, Gabriela M; Liao, Ronglih (2016) Fortune Favors the Prepared: Safety and Efficacy of Allogeneic Hypoxia Preconditioned Mesenchymal Stromal Cells in Primates. Circ Res 118:908-10
Guan, Jian; Mishra, Shikha; Qiu, Yiling et al. (2014) Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity. EMBO Mol Med 6:1493-507
Cheng, Hui-Wen; Fisch, Sudeshna; Cheng, Susan et al. (2014) Assessment of right ventricular structure and function in mouse model of pulmonary artery constriction by transthoracic echocardiography. J Vis Exp :e51041
Hiremath, Pranoti; Bauer, Michael; Aguirre, Aaron D et al. (2014) Identifying early changes in myocardial microstructure in hypertensive heart disease. PLoS One 9:e97424
Liao, Ronglih (2014) Worming along in amyloid cardiotoxicity. Blood 123:3525-6
Hiremath, Pranoti; Bauer, Michael; Cheng, Hui-Wen et al. (2014) Ultrasonic assessment of myocardial microstructure. J Vis Exp :e50850
Guan, Jian; Mishra, Shikha; Shi, Jianru et al. (2013) Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity. Basic Res Cardiol 108:378
Bauer, Michael; Cheng, Susan; Unno, Kazumasa et al. (2013) Regional cardiac dysfunction and dyssynchrony in a murine model of afterload stress. PLoS One 8:e59915
Tsukamoto, Kosuke; Mani, D R; Shi, Jianru et al. (2013) Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease. Proc Natl Acad Sci U S A 110:17023-8

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