Molecular and Cellular Mechanisms of Neonatal Cardiac Development and Repair

新生儿心脏发育和修复的分子和细胞机制

• 批准号: 9024262
• 负责人: Vahid Serpooshan
• 金额: $ 10.25万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9024262
• 关键词: Adult; Animals; Biological Assay; Biology; Biomedical Engineering; Birth; Cardiac; Cardiac Myocytes; Cardiac development; Cardiovascular Physiology; Cells; Cellular biology; Cessation of life; Collagen; Congenital Heart Defects; Data; Development; Devices; Disease; Embryo; Embryonic Development; Engineering; Etiology; Family suidae; Goals; Growth; Healed; Heart; Heart Abnormalities; Heart Diseases; Heart Injuries; Image; In Vitro; Infant; Infarction; Injury; Life; MEKs; Mediating; Mediator of activation protein; Mentors; Molecular; Molecular and Cellular Biology; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Neonatal; Operative Surgical Procedures; Outcome; Physiological; Population; Population Sizes; Process; Proliferating; Property; Recruitment Activity; Regenerative response; Regulation; Reporter; Research; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Site; Staging; Stem cells; Structure; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; Transforming Growth Factor beta; Transgenic Mice; Work; base; cardiac regeneration; cardiac repair; cardiogenesis; career; career development; fetal; genome-wide; healing; improved; in vivo; injured; macromolecule; medical schools; mouse model; multidisciplinary; neonate; novel; novel therapeutics; prenatal; progenitor; programs; repaired; response; small molecule; targeted delivery

 DESCRIPTION (provided by applicant): 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 TGFβ 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 TGFβ 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.

 描述（由申请人提供）：本提案描述了一个为期五年的职业发展计划，以准备候选人，博士Vahid Serpooshan，职业生涯作为一个独立的调查员。该计划将建立在Serpooshan博士作为生物工程科学家的多学科背景基础上，通过提供心脏发育相关的细胞和分子生物学专业知识，在心脏细胞生物学方面进行培训。拟议研究的主要目标是确定新生儿心脏发育的关键机制，可以通过工程补丁来调节缺血性心脏损伤后哺乳动物心脏的发育和修复。PI将在斯坦福大学医学院接受Sean Wu博士和丹尼尔伯恩斯坦博士的指导。吴博士在研究胚胎发育过程中调节心脏谱系定型的机制以及发育和疾病中心脏祖细胞的生物学方面拥有广泛的专业知识。伯恩斯坦博士是斯坦福大学小动物外科和成像设施的主任，他的研究重点是正常生理状态和疾病状态下心血管功能的调节。 我们小组和其他人最近的研究结果表明，新生哺乳动物心脏具有几种进化上保守的心肌再生机制，包括激活定向祖细胞和/或心肌细胞增殖。然而，这些过程背后的细胞/分子机制以及它们是否可以用于修复新生儿心脏仍然难以捉摸。我们的初步数据表明，在新生小鼠中存在TGFβ和MEK信号调节的Nkx2.5+成心肌细胞群体，具有增殖和分化为心肌细胞的潜力。在拟议的研究中，我将测试假设，即新生儿心脏中存在基于细胞的再生反应，可以通过生物工程心脏贴片递送小分子来招募，用于治疗心肌损伤。这项研究的结果预计将产生积极的转化影响，因为它们将为成年哺乳动物心脏的治疗干预引入一种新的无细胞递送方法。我的具体目标是：目标1：确定Nkx2.5+心肌细胞群体及其在新生小鼠心脏中的功能。Nkx2.5 enh-Cre/eGFP报告基因小鼠模型将用于鉴定新生心脏中活化的Nkx2.5心肌细胞祖细胞。目的2：探讨Nkx2.5+心肌细胞增殖和分化的信号通路。TGFβ和MEK信号通路的小分子调节将用于诱导新生Nkx 2.5+成心肌细胞的扩增和心肌样分化。目的3：研究Nkx2.5成心肌细胞和发育信号在缺血性心脏损伤后介导心脏修复中的作用。我将评估缺血性损伤后心肌细胞群体大小的变化及其对信号通路刺激的反应。