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死亡的主要原因，这是由于不能对缺血性损伤进行治疗。 成年人来代替心脏病发作后失去的心肌。相比之下，新生哺乳动物具有 短暂但强大的完全功能性心脏再生能力。新生儿心脏再生 啮齿类动物依赖于预先存在的心肌细胞（CM）的增殖，突出了 了解CM细胞周期调控。这种再生能力在出生后不久就丧失了， CM经历细胞周期停滞、多倍化和肥大生长。我提出的长期目标是 研究的目的是确定介导哺乳动物心脏再生能力丧失的生理触发因素， 潜力在这个建议中，我们建立在我们最近的发现基础上，表明联合抑制甲状腺激素， 出生后发育期间激素（TH）和肾上腺素能受体（AR）信号传导增加CM增殖， 延迟多倍化，促进老年幼年小鼠心脏功能再生。尽管 这些发现的意义，这些途径下游的细胞和分子机制影响 CM细胞分裂仍不清楚。虽然已知TH和AR信号传导促进CM肥大性生长，但 CM大小和细胞周期控制之间的相互关系还没有很好地理解。我们的核心假设是， 出生后TH和AR信号相互作用驱动CM肥大生长并限制增殖 潜力我们正在开创数字全息显微镜的应用， CM体积响应于激素刺激的变化，具有单细胞分辨率。我们正在使用 该技术用于解决CM肥大性生长是否抑制细胞周期进展和分裂。我们将测试我们的 目的1：确定TH和AR信号相互作用如何促进CM 肥厚目的2：明确TH和AR信号相互作用如何抑制CM增殖。目标3：确定 TH和AR信号转导下游的分子靶点调节CM肥大和增殖。的结果 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， 成年人的心脏再生能力这项SuRE优先奖将资助大约40项研究 本科生和8名硕士生在四年的课程，包括许多少数民族学员在圣何塞 州立大学，一个主要致力于培养本科生和硕士学位的机构 少数民族学生人数不足。本科生将执行大部分拟议的工作， 高级研究生和PI的培训和指导。这笔资金将允许PI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.