Neurohumoral Interactions Coordinating Mammalian Cardiomyocyte Size and Proliferation

项目摘要 在美国，缺血性损伤后的心力衰竭仍然是导致死亡的主要原因，这是因为 成年人类在心脏病发作后替换丢失的心肌。相比之下，新生哺乳动物拥有一种 短暂但强大的完全功能心脏再生能力。新生儿的心脏再生 啮齿动物依赖于预先存在的心肌细胞(CM)的增殖，强调了 了解CM细胞周期调控。这种再生能力在出生后不久就会丧失，当大多数 CMS经历了细胞周期停滞、多倍化和肥大生长。我提出的长期目标是 研究旨在确定导致哺乳动物心脏再生能力后天丧失的生理诱因 潜力。在这项提案中，我们以我们最近的发现为基础，证明了对甲状腺的联合抑制 激素(TH)和肾上腺素能受体(AR)信号在出生后发育过程中促进CM增殖， 延缓多倍体，并促进老年幼鼠心脏功能再生。尽管 这些发现的意义，这些通路下游影响的细胞和分子机制 CM细胞分裂仍不清楚。虽然已知TH和AR信号促进CM肥大生长，但 CM大小和细胞周期控制之间的相互关系还不是很清楚。我们的中心假设是 出生后TH和AR信号相互作用推动心肌肥大生长并限制增殖 潜力。我们正在率先应用数字全息显微镜来可视化三维 以单细胞分辨率实时响应激素刺激的CM体积的变化。我们正在使用 这项技术解决了如果CM肥大生长抑制细胞周期进展和分裂。我们将测试我们的 以下具体目标的假设：目标1：确定TH和AR信号相互作用如何促进CM 肥大。目的2：明确TH和AR信号相互作用如何抑制CM的增殖。目标3：确定 TH和AR信号下游调控心肌肥大和增殖的分子靶点。结果是 这些研究有望揭示促进细胞和分子机制的新见解。 哺乳动物心脏再生能力的丧失，这可能有助于提供新的治疗策略来改善 成年人类的心脏再生能力。这一肯定第一的奖项将资助大约40名研究人员。 在四年的课程中，本科生和8名硕士学生，包括圣何塞的许多少数族裔实习生 州立大学，主要是本科和硕士级别的机构，致力于培训 代表不足的少数族裔学生。本科生将完成大部分拟议的工作， 来自高级研究生和PI的培训和指导。这笔资金将使私家侦探继续 在研究方面建立良好的记录，为本科生提供有意义的科学经验， 并加强圣何塞州立大学的研究环境。

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.