Several lines of evidence have linked all-trans retinoic acid (atRA) with inhibition of hypertrophy and hyperplasia in cardiomyocytes, vascular smooth muscle cells, and fibroblasts. We have generated several mouse models in which myocyte intracellular retinoid signaling is obliterated, and have demonstrated that retinoids play a pivotal role in maintaining cardiac function during adulthood. However, the intracellular mechanism by which retinoids function in the mature myocardium are vastly unknown. In order to gain insight into the retinoid- mediated signaling in the myocardium, we have evaluated the role of several candidate signal transducers in the myocytes and have recently discovered that mutation of a novel orphan type I - GPCR rescues dilated cardiomyopathy and ventricular contractility upon retinoid deficiency in vivo. We hypothesize that the retinoid and 20RH pathways converge in the myocytes to regulate cardiac function;and propose the following Specific Aims:
Specific Aim 1. To determine the existence of cross regulation between the retinoid receptors and the 20RH type I-GPCR;
Specific Aim 2. To asses whether 20RH and retinoid-receptor pathways converge in the regulation of cardiac myocyte contractility;
Specific Aim 3 will analyze the signaling downstream of 20RH. Finally, Specific Aim 4 will establish whether down-regulation of 20RH can be used as an exportable therapeutic system in diverse models of myocyte dysfunction. Completion of this proposal will establish the molecular basis for a novel link between nuclear receptors and GPCR signaling in cardiac failure and demonstrate different levels of regulation among these two pathways (cross-regulation and downstream convergence). In addition, since mutation of 20RH does not display a basal phenotype, systems that reduce the activity of 20RH may be an excellent novel therapeutic target. Beyond the scope of this proposal, is the identification of endogenous ligands and chemical agonists/antagonists for 20RH

Public Health Relevance

Here we propose the study of the molecular mechanism by which reduction in GPCR signaling rescues abnormal cardiac function. Completion of this proposal will set up the groundwork for novel therapies to cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL086879-01A2
Application #
7585028
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Mintzer, Keith A
Project Start
2009-01-15
Project End
2012-12-31
Budget Start
2009-01-15
Budget End
2009-12-31
Support Year
1
Fiscal Year
2009
Total Cost
$492,515
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Diez-Cuñado, Marta; Wei, Ke; Bushway, Paul J et al. (2018) miRNAs that Induce Human Cardiomyocyte Proliferation Converge on the Hippo Pathway. Cell Rep 23:2168-2174
Díaz-Trelles, Ramón; Scimia, Maria Cecilia; Bushway, Paul et al. (2016) Notch-independent RBPJ controls angiogenesis in the adult heart. Nat Commun 7:12088
Mahmoudi, Morteza; Zhao, Mingming; Matsuura, Yuka et al. (2016) Infection-resistant MRI-visible scaffolds for tissue engineering applications. Bioimpacts 6:111-5
Serpooshan, Vahid; Mahmoudi, Morteza; Zhao, Mingming et al. (2015) Protein Corona Influences Cell-Biomaterial Interactions in Nanostructured Tissue Engineering Scaffolds. Adv Funct Mater 25:4379-4389
Serpooshan, Vahid; Sivanesan, Senthilkumar; Huang, Xiaoran et al. (2015) [Pyr1]-Apelin-13 delivery via nano-liposomal encapsulation attenuates pressure overload-induced cardiac dysfunction. Biomaterials 37:289-98
Wei, Ke; Serpooshan, Vahid; Hurtado, Cecilia et al. (2015) Epicardial FSTL1 reconstitution regenerates the adult mammalian heart. Nature 525:479-85
Serpooshan, Vahid; Ruiz-Lozano, Pilar (2014) Ultra-rapid manufacturing of engineered epicardial substitute to regenerate cardiac tissue following acute ischemic injury. Methods Mol Biol 1210:239-48
Nam, Joseph; Onitsuka, Izumi; Hatch, John et al. (2013) Coronary veins determine the pattern of sympathetic innervation in the developing heart. Development 140:1475-85
Serpooshan, Vahid; Zhao, Mingming; Metzler, Scott A et al. (2013) The effect of bioengineered acellular collagen patch on cardiac remodeling and ventricular function post myocardial infarction. Biomaterials 34:9048-55
Llagostera, Esther; Alvarez Lopez, Maria Jesus; Scimia, Cecilia et al. (2012) Altered ýý-adrenergic response in mice lacking myotonic dystrophy protein kinase. Muscle Nerve 45:128-30

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