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

项目总结/摘要 本提案描述了一个为期5年的NIH/R 01-早期研究者申请，用于开发我的 新生儿心血管医学的学术和研究生涯。我已经完成了住院医师培训， 德克萨斯大学的儿科学和德克萨斯大学的新生儿-围产期医学的子专业奖学金培训 波士顿儿童医院，哈佛大学。2015年，我完成了分子，细胞和 综合生理学，通过专业和高级研究培训（星星）计划，在加州大学洛杉矶分校根据 王一斌博士的指导。在2016年，我过渡到我的独立实验室， 新生儿/先天性心脏病研究计划。利用基因组学和分子生物学方面的技能 结合我在新生儿心脏成熟的论文研究中学到的新见解，我的目标是开发一个 研究计划，重点是围产期心腔生长和对外界压力的反应， 先天性心脏病（CHD）我的研究成果与我不断增长的临床技能相辅相成 在照顾早产儿和新生儿与冠心病作为儿科助理教授在美泰 加州大学洛杉矶分校儿童医院我也是加州大学洛杉矶分校CHD-BioCore的创始人和主任。 围产期心脏成熟及其调控网络是心脏发育的一个非常缺乏研究的领域， 发育，但在新生儿CHD的护理中具有潜在的重大影响。拟议研究 着重于细胞间信号在围产期心腔发育调节中的作用 胎儿向新生儿过渡期间的成熟和对缺氧的反应，这是一个研究不足但至关重要的窗口， 心脏生长，特别是在CHD的情况下。在我以前的工作中，我着手解决这个重要的差距， 通过对围产期心脏转录组进行全基因组分析，通过这些研究，我 揭示了一种新的电路，涉及Wnt 11信号和缺氧调节室特异性生长。我进一步 建立了Wnt 11调节心肌细胞（CMC）增殖可能是通过RB 1调节在正常 和缺氧转变以及紫绀型CHD。在这份提案中，我计划建立一个病理影响 以及介导Wnt 11/Rb 1调节室特异性CMC增殖的分子基础， 缺氧在AIM 1中，我将确定Wnt 11/Rb 1信号在围产期心腔发育中的作用 使用新产生的可诱导和CMC特异性Wnt 11敲除小鼠模型， 与围产期缺氧暴露相结合。在AIM 2中，我将在新生儿CMC中发现Wnt 11相互作用组， 剖析介导Wnt 11功能的细胞自主信号传导机制。在AIM 3中，我将确定生物学 新发现的信号网络在体内的相关性，并将建立在冠心病的临床相关性。 完成拟议的研究将建立一个新的Wnt 11和缺氧之间的相互作用， 这可能会导致对患有CHD的新生儿采取特定的腔室方法。加州大学洛杉矶分校提供了一个理想的科学 环境，以实现拟议的研究和职业目标，作为一个独立的物理学家，科学家。

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.