This proposal describes a five-year career development program to prepare the candidate, Dr. Vahid Serpooshan, for a career as an independent investigator. This program will build upon Dr. Serpooshan's multidisciplinary background as a bioengineer scientist, trained in cardiac cellular biology, by providing expertise in cellular and molecular biology underlying heart development. The main goal of the proposed research is to identify the key mechanisms underlying neonatal heart development that could be exploited - via an engineered patch - to regulate mammalian heart development and repair, following ischemic heart injury. The PI will be mentored at Stanford Medical School by Drs. Sean Wu and Daniel Bernstein. Dr. Wu has extensive expertise in investigating the mechanisms regulating cardiac lineage commitment during embryonic development and the biology of cardiac progenitor cells in development and disease. Dr. Bernstein is the director of the small animal surgery and imaging facilities at the Stanford, and his research focuses on regulation of cardiovascular function in both normal physiologic states as well as in disease states. Recent findings by our group and others have demonstrated that neonatal mammalian hearts possess several evolutionarily conserved mechanisms for myocardial regeneration, including activation of committed progenitors and/or cardiomyocytes proliferation. However, the cellular/molecular mechanisms underlying these processes and whether they can be employed to repair neonatal heart remains elusive. Our preliminary data demonstrates the existence of a population of TGF? and MEK signaling-regulated Nkx2.5+ cardiomyoblasts in neonatal mice with the potential to proliferate and differentiate into cardiomyocytes. In the proposed study, I will test the hypothesi that a cell-based regenerative response is present in the neonatal heart that can be recruited, via a bioengineered cardiac patch delivery of small molecules, for the treatment of myocardium injury. Results from this research are expected to have positive translational impact as they will introduce a novel cell-free delivery approach for therapeutic interventions in the adult mammalian heart.
My specific aims are:
Aim 1 : Identify an Nkx2.5+ cardiomyoblast population and their function in the neonatal mouse heart. An Nkx2.5 enh-Cre/eGFP reporter mouse model will be used to identify the activated Nkx2.5 cardiomyogenic progenitors in neonatal heart.
Aim 2 : Determine the signal and pathways involved in Nkx2.5+ cardiomyoblasts proliferation and differentiation. Small molecule regulation of TGF? and MEK signaling pathways will be used to induce the expansion and cardiomyogenic differentiation of the neonatal Nkx2.5+ cardiomyoblasts.
Aim 3 : Examine the role of Nkx2.5 cardiomyoblasts and developmental signals to mediate cardiac repair following ischemic heart injury. I will assess the changes to the cardiomyoblast population size and their response to signaling pathway stimulation following ischemic injury.
Application Title: Molecular and cellular mechanisms of neonatal cardiac development and repair Project Narrative Nearly 70% of infant heart disease-related deaths occur neonatally (<28 days old). In this research we aim at understanding why the heart ability to repair suddenly and dramatically stops in neonates during the first few days after birth. The proposed study tries to identify what cellular and molecular factors are involved in heart development and repair pre- and right after birth, that are absent in neonates and adults. Using a cardiac patch device, we will try to reintroduce these effective factors into the neonate hearts that are suffering from congenital disease or sudden injures after birth. Thus, we can help the neonate heart to heal as much as if the heart were in fetal life again.
