TBX5 and Histone Deacetylases in Cardiogenesis

心脏发生中的 TBX5 和组蛋白脱乙酰酶

• 批准号: 6945066
• 负责人: CATHY J HATCHER
• 金额: $ 14.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-08 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6945066
• 关键词: Holt Oram syndrome; amidohydrolases; cardiogenesis; cell proliferation; chick embryo; developmental genetics; genetic promoter element; histones; nonmammalian vertebrate embryology; transcription factor

DESCRIPTION (provided by applicant): The objective of this Mentored Minority Faculty Development (K01) Award is to develop Dr. Cathy Hatcher's career as an independent scientist dedicated to investigate cardiac development. Cardiac development is a complex process that can be wrought with defects. Congenital heart defects account for 0.5-1 % of all live births. Mutations in TBX5 cause Holt-Oram syndrome, an inherited disorder characterized by structural cardiac defects. The TBX5 transcription factor plays an important role in cardiogenesis. It can act as a cellular growth arrest signal to inhibit cell proliferation in vitro and in vivo. In this proposal, we demonstrate that mRNA and protein expression of histone deacetylase 2 (HDAC2) is upregulated byTBXS. The specific goal of the proposed research is to characterize the mechanisms underlying the interactions between and the functional contributions of TBX5 and the HDAC2 gene. We hypothesize that TBX5- dependent regulation of HDAC2 participates in TBX5 regulation of cardiomyocyte proliferation and cardiogenesis. Dr. Hatcher proposes to acquire new structural, biochemical, genomic and molecular genetic knowledge and skills to explore this critical pathway and also to determine the contribution of TBX5 along with HDAC2 to cellular proliferation and cardiogenesis. We propose: (1) to determine if TBX5 regulates HDAC2 expression through direct interactions with the HDAC2 promoter (2) to determine which TBX5 domains are required for regulation of HDAC2 expression and (3) to determine if HDAC2 overexpression is sufficient to recapitulate the effects of TBX5 on cardiac cell proliferation in vitro and in vivo. Elucidating TBX5 and HDAC2 dependent pathways in cardiac development and their contribution to regulation of cell proliferation will define key genetic events that can go awry in individuals with congenital heart malformations.

描述（由申请人提供）： 这一指导的少数族裔教师发展（K01）奖的目的是发展凯茜·哈切尔（Cathy Hatcher）博士的职业生涯，致力于研究心脏发展。心脏发展是一个复杂的过程，可以与缺陷进行处理。先天性心脏缺陷占所有活产的0.5-1％。 TBX5突变引起Holt-Oram综合征，这是一种以结构性心脏缺陷为特征的遗传疾病。 TBX5转录因子在心脏发生中起重要作用。它可以充当细胞生长停滞信号，可在体外和体内抑制细胞增殖。在此提案中，我们证明了组蛋白脱乙酰基酶2（HDAC2）的mRNA和蛋白质表达上调BYTBXS。拟议的研究的具体目标是表征TBX5和HDAC2基因之间相互作用和功能贡献的机制。我们假设HDAC2的TBX5依赖性调节参与了心肌细胞增殖和心脏发生的TBX5调节。 Hatcher博士建议获取新的结构，生化，基因组和分子遗传知识和技能，以探索这一关键途径，并确定TBX5以及HDAC2对细胞增殖和心脏病的贡献。我们提出：（1）确定TBX5是否通过与HDAC2启动子直接相互作用（2）来调节HDAC2表达，以确定调节HDAC2表达的调节所需的TBX5域需要哪些TBX5域，并且（3）以确定HDAC2过表达是否足以概括TBX5对心脏细胞的效果是否对心脏细胞的效果进行了体内效率和Viviv。阐明心脏发育中的TBX5和HDAC2依赖性途径及其对细胞增殖的调节的贡献将定义关键的遗传事件，而先天性心脏畸形的个体可能会出现问题。