During the period of the past award, we have developed a transgenic mouse that targets Cre-recombinase to the epicardium. This is a unique model system that we have used to demonstrate that conditional mutation of the retinoid receptor alpha (RXR1) in the epicardium affects cardiac morphogenesis and impairs embryonic survival. This mutation also uncovered a novel role of nuclear receptors in coronary arteriogenesis. We have subsequently determined that the 2-catenin gene acts downstream of the RXR1 pathway and we have generated data demonstrating that mutation of 2-catenin in the epicardium impairs cardiac morphogenesis by reducing cardiac cell proliferation and coronary vessel formation. Here we hypothesize that a Wnt/2 catenin pathway in the epicardium regulates key steps in cardiac development, including cell proliferation in the myocardium and the formation of the coronary vasculature. To demonstrate this hypothesis, we propose three independent genetic approaches that address the following specific aims:
Aim 1 will determine the role of epicardial 2-catenin in cell fate specification and maturation of epicardial derivatives ex vivo and in vivo using time-lapse analysis of explanted tissues, lineage tracing, and mechanistic studies in epicardial-2-catenin mutant mice.
In Aim 2 we will determine whether Wnt activity regulates the formation of the coronary arteries and the expansion of the compact zone. To address this question, we will use a genetic strategy to block 2-catenin nuclear translocation and analyze signaling downstream of Wnt in the epicardium.. Finally, in Aim 3 we will determine whether 2 catenin is a functional mediator of RXR1 signaling. As a proof of principle for this hypothesis, we propose the rescue of the RXR1 phenotype by interbreeding the RXR1 mutant mice with the conditional 2 catenin/loxP (ex3) mouse, resulting in mice with constitutively active 2 catenin in the epicardium. Completion of this proposal will unravel the mechanisms of retinoid/2 catenin signaling in coronary formation and ventricular compaction and might offer the potential for therapeutic interventions to ameliorate or even treat coronary disorders that are leading causes of mortality.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065484-08
Application #
7804621
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2000-07-01
Project End
2010-12-31
Budget Start
2010-05-01
Budget End
2010-12-31
Support Year
8
Fiscal Year
2010
Total Cost
$477,500
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
Wei, Ke; Díaz-Trelles, Ramon; Liu, Qiaozhen et al. (2015) Developmental origin of age-related coronary artery disease. Cardiovasc Res 107:287-94
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

Showing the most recent 10 out of 17 publications