Our program project addresses the mechanisms of processes triggered by stresses on the heart that are adaptive and offset the stressor or are maladaptive and exacerbate the stressor leading to decompensation and heart failure. The theme of the program that ties the projects together is our hypothesis that alterations at the level of cardiac sarcomeres and costameres are primary and critical mechanisms in these processes and the transition from adaptation to maladaptatlon. The program has four highly interactive and synergistic projects approaching our hypothesis with perspectives and approaches that complement and reinforce each other. Administrative, Animal, and Proteomics/ Analytical Biochemistry Cores support these projects and coordinate their activities to ensure synergy and cohesion among these approaches. Objectives of Project 1 (Solaro) emphasize phospho-protein analysis and molecular mechanisms of altered sarcomeric protein function in response to metabolic signaling activation via AMPK/Paki (with emphasis on the evolution and rescue of familial hypertrophic cardiomyopathy (FHC);and via PKCe, and with emphasis on dilated cardiomyopathy, novel phosphorylation sites and on rescue. In Project 2 (Russell/Samarel) the overall objective is to test the hypothesis that mechanical strain regulates cell lengthening by phosphorylation of focal adhesion kinase at the costamere leading to actin capping by CapZ. In Project 3 (LewandoskI), the overall objective is to elucidate the potential for, and the extent to which myofilament modifications induce changes in metabolic phenotype and elucidate adaptive and/or cardioprotective shifts in metabolic pathways, In Project 4 (de Tombe) the major objective is to determine the structure-function relations of sarcomeric protein phosphorylation and myofilament function in the development of congestive heart failure (CHF) in a well-established model of CHF in the guinea-pig secondary to pressure- or volume overload. Approaches to these objectives include novel animal models, determination of cardiac hemodynamics and metabolism with NMR, mechanical studies at the level of the heart, myocytes, and myofibrils, proteomics, and molecular studies at the protein level. The approaches are directly related to the goal of translating findings in the projects to the diagnosis and to the development of novel therapies in familial and acquired cardiomyopathies and heart failure. Familial and acquired heart failure are among the most prevalent disorders of the heart and responsible for the majority of hospital admissions in the USA. Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL062426-15
Application #
8629546
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Evans, Frank
Project Start
2000-06-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
15
Fiscal Year
2014
Total Cost
$2,530,550
Indirect Cost
$703,829
Name
University of Illinois at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Zak, Taylor J; Koshman, Yevgenia E; Samarel, Allen M et al. (2017) Regulation of Focal Adhesion Kinase through a Direct Interaction with an Endogenous Inhibitor. Biochemistry 56:4722-4731
Ryba, David M; Li, Jieli; Cowan, Conrad L et al. (2017) Long-Term Biased ?-Arrestin Signaling Improves Cardiac Structure and Function in Dilated Cardiomyopathy. Circulation 135:1056-1070
Ait-Mou, Younss; Zhang, Mengjie; Martin, Jody L et al. (2017) Impact of titin strain on the cardiac slow force response. Prog Biophys Mol Biol 130:281-287
Karam, Chehade N; Warren, Chad M; Henze, Marcus et al. (2017) Peroxisome proliferator-activated receptor-? expression induces alterations in cardiac myofilaments in a pressure-overload model of hypertrophy. Am J Physiol Heart Circ Physiol 312:H681-H690
Li, King-Lun; Ghashghaee, Nazanin Bohlooli; Solaro, R John et al. (2016) Sarcomere length dependent effects on the interaction between cTnC and cTnI in skinned papillary muscle strips. Arch Biochem Biophys 601:69-79
de Tombe, Pieter P; ter Keurs, Henk E D J (2016) Cardiac muscle mechanics: Sarcomere length matters. J Mol Cell Cardiol 91:148-50
Broughton, K M; Li, J; Sarmah, E et al. (2016) A myosin activator improves actin assembly and sarcomere function of human-induced pluripotent stem cell-derived cardiomyocytes with a troponin T point mutation. Am J Physiol Heart Circ Physiol 311:H107-17
Paudyal, Anju; Dewan, Sukriti; Ikie, Cindy et al. (2016) Nuclear accumulation of myocyte muscle LIM protein is regulated by heme oxygenase 1 and correlates with cardiac function in the transition to failure. J Physiol 594:3287-305
Siddiqui, Jalal K; Tikunova, Svetlana B; Walton, Shane D et al. (2016) Myofilament Calcium Sensitivity: Consequences of the Effective Concentration of Troponin I. Front Physiol 7:632
Abraham, Dennis M; Davis 3rd, Robert T; Warren, Chad M et al. (2016) ?-Arrestin mediates the Frank-Starling mechanism of cardiac contractility. Proc Natl Acad Sci U S A 113:14426-14431

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