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.