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（由应用程序提供）：该提案描述了一项为期五年的职业发展计划，以准备候选人Vahid Serpooshan博士作为独立调查员的职业。该计划将基于Serpooshan博士的多学科背景，作为一名生物工程学的科学家，通过提供心脏发育的细胞和分子生物学专业知识，接受了心脏细胞生物学的培训。拟议研究的主要目的是确定新生儿心脏发育的关键机制，这些机制可以通过工程贴片进行探索，以调节缺血性心脏损伤后调节哺乳动物的心脏发育和修复。 Drs将在斯坦福医学院打电话给PI。肖恩·吴（Sean Wu）和丹尼尔·伯恩斯坦（Daniel Bernstein）。 Wu博士在研究胚胎发育过程中恢复心脏谱系承诺的机制和心脏祖细胞在发育和疾病中的生物学方面具有广泛的专业知识。 Bernstein博士是斯坦福大学小型动物外科和成像设施的主任，他的研究重点是调节正常生理状态以及疾病状态的心血管功能。我们小组和其他人的最新发现表明，新生儿哺乳动物心脏具有多种进化的心肌再生机制，包括激活忠实的祖细胞和/或心肌细胞增殖。但是，这些过程的基础上的细胞/分子机制以及是否可以使用它们来修复新生儿心脏仍然难以捉摸。我们的初步数据表明，在新生儿小鼠中，TGFβ和MEK信号调节的NKX2.5+心肌细胞的存在，有可能增殖并分化为心肌细胞。在拟议的研究中，我将检验假设，即在新生儿心脏中提出了基于细胞的再生反应，可以通过小分子的生物工程性心脏贴剂递送来治疗心肌损伤。这项研究的结果预计将产生积极的翻译影响，因为它们将引入一种新型的成年哺乳动物心脏治疗干预措施的新型无细胞递送方法。我的具体目的是：目标1：确定NKX2.5+心肌细胞种群及其在新生小鼠心脏中的功能。 NKX2.5 ENH-CRE/EGFP记者小鼠模型将用于识别新生儿心脏中活化的NKX2.5心肌生成祖细胞。 AIM 2：确定NKX2.5+心肌马力的信号和途径增殖和分化。 TGFβ和MEK信号通路的小分子调节将用于诱导新生儿NKX2.5+心脏肌瘤的膨胀和心肌生成分化。 AIM 3：检查NKX2.5心肌细胞的作用和开发信号以介导性心脏损伤后介导心脏修复。我将评估心肌细胞种群大小的变化及其对缺血性损伤后对信号通路刺激的反应。