Novel Mechanisms in Chamber-Specific Regulation of Perinatal Heart Growth
Abstract
Congenital heart diseases CHD can be contributed both inherent genetic defects as well as environmental stresses. While most of the studies focus on genes and genetic basis of CHD, relatively little is known about the effect of stress induced signaling on the progression of CHD. In studies leading to this proposal, we discovered two stress molecules (p38 and IRE1), previously only known to participate stress-induced cellular responses in heart muscle cells, also have a significant impact on right ventricle specific remodeling in newborn hearts. More interestingly, these two molecules are affected by hypoxemia in experimental animals and human subjects with Tetralogy of Fallot (TOF) under hypoxic conditions. Therefore, we hypothesize that normal maturation of right ventricle requires p38/IRE1/Xbp1 stress signaling during perinatal natal development, and this signaling network is disturbed by hypoxemia and contributes to cardiac abnormalities in TOF with cyanosis. In this proposal, we plan to rigorously investigate by (1) determining the functional impact of p38 activities on myocyte growth, proliferation, and programmed cell death in the right vs. left ventricle in perinatal heart normal and hypoxemia stress; (2) unraveling the molecular and cellular mechanisms underlying chamber specific p38-IRE1-Xbp1 signaling in perinatal hearts; and (3) establishing clinical relevance of p38-IRE1-Xbp1 signaling network in right ventricle abnormalities in TOF. The outcome of this study will fill a critical gap in our knowledge to chamber-specific cardiac signaling and its role in abnormal postnatal growth in CHD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810164
Entities
People
- Yibin Wang
Organizations
- United States Army
- University of California, Los Angeles