Novel Gene-Environment Regulatory Circuit in Chamber Specific Growth of Perinatal Heart

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT This proposal describes a 5-year NIH/R01-Early Stage Investigator Application for the development of my academic and investigative career in neonatal cardiovascular medicine. I have completed a residency training in Pediatrics at University of Texas and a subspecialty fellowship training in Neonatal–Perinatal Medicine at Boston Children's Hospital, Harvard University. In 2015, I completed a PhD program in Molecular, Cell & Integrated Physiology, through the Specialty and Advanced Research Training (STAR) Program, at UCLA under the mentorship of Dr. Yibin Wang. In 2016, I transitioned to my independent laboratory to establish the Neonatal/Congenital Heart Research Program. Using the acquired skills in genomics and molecular biology combined with new insights learnt from my thesis research in neonatal heart maturation, I aim to develop a research program focusing on perinatal cardiac chamber growth and response to external stress in the context of congenital heart defects (CHDs). My research efforts have been complemented with my growing clinical skills in taking care of preterm infants and newborns with CHDs as an Assistant Professor of Pediatrics at Mattel Children's Hospital at UCLA. I am also the founder and the director of the CHD-BioCore at UCLA. Perinatal heart maturation and its regulatory network is a very much-understudied area of cardiac development, but with potential major implications in the care of neonates with CHDs. The proposed research focuses on the role of intercellular signaling in the developmental regulation of perinatal heart chamber maturation and responses to hypoxia during fetal to neonatal transition, an understudied, but critical, window for cardiac growth, particularly, in the context of a CHD. In my previous work, I set out to address this important gap of knowledge by employing genome-wide analysis of perinatal cardiac transcriptome. From these studies, I uncovered a novel circuit involving Wnt11 signaling and hypoxia in regulating chamber specific growth. I further established that Wnt11 regulates cardiomyocyte (CMC) proliferation likely through RB1 regulation during normal and hypoxic transition as well as in cyanotic CHDs. In this proposal, I plan to establish the pathological impact and the molecular basis mediating Wnt11/Rb1 regulation of chamber specific CMC proliferation in response to hypoxia. In AIM 1, I will determine the role of Wnt11/Rb1 signaling in perinatal cardiac chamber development and hypoxia response using newly generated inducible and CMC specific Wnt11 knockout mouse model in combination with perinatal hypoxia exposure. In AIM 2, I will discover Wnt11 interactome in neonatal CMC to dissect cell-autonomous signaling mechanisms mediating Wnt11 function. In AIM3, I will determine the biological relevance of the newly discovered signaling network in vivo and will establish the clinical relevance in CHDs. Accomplishing the proposed studies will establish a novel interactome between Wnt11 and hypoxia that may potentially lead to chamber specific approaches for newborns with CHDs. UCLA provides an ideal scientific environment to accomplish the proposed research and career goals as an independent physician–scientist.