Neurohumoral Interactions Coordinating Mammalian Cardiomyocyte Size and Proliferation

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Project Summary Heart failure after ischemic injury remains a leading cause of death in the United States due to the inability of adult humans to replace lost cardiac muscle after heart attack. In contrast, newborn mammals possess a transient but robust capacity for complete functional heart regeneration. Cardiac regeneration in neonatal rodents relies on the proliferation of pre-existing cardiomyocytes (CM), highlighting the importance of understanding CM cell cycle regulation. This regenerative capacity is lost shortly after birth when the majority of CMs undergo cell cycle arrest, polyploidization, and hypertrophic growth. The long-term goal of my proposed research is to define the physiological triggers that mediate the postnatal loss of mammalian heart regenerative potential. In this proposal, we build upon our recent discovery demonstrating that combined inhibition of thyroid hormone (TH) and adrenergic receptor (AR) signaling during postnatal development increases CM proliferation, delays polyploidization, and promotes heart functional regeneration in older juvenile mice. Despite the significance of these findings, the cellular and molecular mechanisms downstream of these pathways impacting CM cell division remain unclear. While TH and AR signaling are known to promote CM hypertrophic growth, the interrelationship between CM size and cell cycle control is not well understood. Our central hypothesis is that TH and AR signaling interactions after birth drive CM hypertrophic growth and limits proliferative potential. We are pioneering the application of digital holographic microscopy to visualize three-dimensional changes in CM volume in response to hormonal stimulation in real-time with single cell resolution. We are using this technology to resolve if CM hypertrophic growth inhibits cell cycle progression and division. We will test our hypothesis in the following specific aims: Aim 1: Determine how TH and AR signaling interactions promote CM hypertrophy. Aim 2: Define how TH and AR signaling interactions inhibit CM proliferation. Aim 3: Identify the molecular targets downstream of TH and AR signaling regulating CM hypertrophy and proliferation. The results of these studies are expected to reveal new insights into the cellular and molecular mechanisms facilitating the loss of heart regenerative capacity in mammals, which may help inform novel treatment strategies to improve heart regenerative capacity in adult humans. This SuRE-First award will fund the research of approximately 40 undergraduates and 8 M.S students over the course of four years, including many minority trainees at San Jose State University, a primarily undergraduate and Master’s-level institution committed to training under-represented minority students. Undergraduates will perform the majority of the proposed work, with training and mentorship from senior graduate students and the PI. This funding would allow the PI to continue to develop a strong track record in research, give meaningful scientific experiences to undergraduate students, and strengthen the research environment at San Jose State University.