The Role of Cyclin A in Cardiac Development

细胞周期蛋白 A 在心脏发育中的作用

• 批准号: 6756528
• 负责人: Hina W Chaudhry
• 金额: $ 12.89万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6756528
• 关键词: age difference; apoptosis; cardiac myocytes; cell proliferation; cyclin dependent kinase; cyclins; gene induction /repression; genetically modified animals; growth /development; heart; heart enlargement; laboratory mouse

DESCRIPTION (provided by applicant): This is an application for a Mentored Physician Scientist Development Award for Hina W. Chaudhry, M.D. who will be an assistant professor of clinical medicine as of July 1, 2000. She will spend 80 percent of her time in a program of scientific training under the guidance of Dr. Debra Wolgemuth, Professor of Genetics and Development. This training will be driven by a project whose theme is to investigate the role of cyclin A in cardiomyocyte development proliferation, and terminal differentiation. The first specific aim is based on a transgenic mouse model of constitutive cyclin A expression in the heart. This is based on the observation that cyclin A levels in the heart drop precipitously shortly after birth in mice, rats, and humans, coincident with terminal differentiation of the heart. The mouse model has been generated based on the hypothesis that constitutive expression will maintain proliferation through the later phases of development, the neonatal period, and adulthood. The phenotype of these mice will be characterized with respect to heart size, cardiomyocyte hyperplasia/hypertrophy, altered cardiac function, an increase in nuclear ploidy and DNA synthesis, alteration of expression of other cell cycle proteins, apoptosis, and an altered response to injury. The second specific aim seeks to characterize molecular events that occur downstream of cyclin A binding to its kinase partners, cdk2 and cdc2. This is based on the hypothesis that cardiomyocyte cell cycle exit is coordinated by a cascade of inhibition whereby down regulation of cyclin A results in hypophosphorylation of RB or an RB-hke protein, and that constitutive expression of cyclin A in the heart may result in the maintenance of a phosphorylated state of such a protein, thereby resulting in persistent transcription of genes responsible for DNA replication and cell division. The third specific aim seeks to understand the mechanism underlying the down regulation of cyclin A in the heart. Methylation of promoter sequences is a well-established epigenetic modification that can result in gene silencing. Sequences of the cyclin A promoter thought to be crucial for gene transcription will by assayed for methylation and a potential correlation with cell cycle exit will be explored. The pursuit of these specific aims will provide the critical focus during which time the PI will gain an intensive training experience, learning new techniques as well as the methods of scientific inquiry under the immediate supervision of the Sponsor, an internationally recognized expert in the field of cell cycle and developmental biology. In addition to daily interactions with the Sponsor and members of the immediate laboratory, the PI will participate in a series of lectures given by the faculty of Genetics and Development, and participate in seminars through the Department of Medicine. Additionally, the Sponsor holds a series of Work-in-Progress seminars, in which members of the laboratory present intermediate data and receive critical suggestions from other laboratory members and invited faculty. These intellectual resources, combined with the fiscal resources to support theproject which will be provided by the Chairman of Medicine, will enable the PI to develop into an independent investigator by the conclusion of the training period.

描述（由申请人提供）：这是一个指导医生科学家发展奖的申请Hina W。Chaudhry，医学博士他将成为临床医学的助理教授 自2000年7月1日起，她将花80%的时间在遗传学和发展教授黛布拉·沃尔格穆特博士的指导下进行科学培训。该培训将由一个项目驱动，该项目的主题是研究细胞周期蛋白A在心肌细胞发育增殖和终末分化中的作用。 第一个具体目标是基于心脏中组成型细胞周期蛋白A表达的转基因小鼠模型。这是基于观察到小鼠、大鼠和人类出生后不久心脏中的细胞周期蛋白A水平急剧下降，与心脏的终末分化一致。小鼠模型是基于组成型表达将在发育后期、新生期和成年期维持增殖的假设而产生的。这些小鼠的表型将在心脏大小、心肌细胞增生/肥大、改变的心脏功能、细胞核增殖的增加、心肌细胞的增殖和心肌细胞的增殖方面进行表征。 倍性和DNA合成、其他细胞周期蛋白表达的改变、细胞凋亡和对损伤反应的改变。 第二个具体的目标是寻求表征发生在细胞周期蛋白A与其激酶伴侣cdk 2和cdc 2结合下游的分子事件。这是基于这样的假设，即心肌细胞周期的退出是通过级联抑制来协调的，由此细胞周期蛋白A的下调导致RB或RB样蛋白的低磷酸化，并且组成性的细胞周期抑制是通过细胞周期蛋白A的下调来协调的。 心脏中细胞周期蛋白A的表达可导致这种蛋白质的磷酸化状态的维持，从而导致负责DNA复制和细胞分裂的基因的持续转录。 第三个具体目标是试图了解心脏中细胞周期蛋白A下调的机制。启动子序列的甲基化是一种公认的表观遗传修饰，可导致基因沉默。细胞周期蛋白A启动子的序列被认为是基因转录的关键，将通过甲基化和潜在的相关性进行分析。 将探索细胞周期退出。 追求这些特定目标将提供关键重点，在此期间，PI将获得强化培训经验，学习新技术以及在申办方（细胞周期和发育生物学领域的国际公认专家）的直接监督下进行科学探究的方法。除了与申办者和直接实验室成员的日常互动外，PI还将参加遗传学和发育学院举办的一系列讲座，并通过医学系参加研讨会。此外，赞助商举办了一系列的工作进展研讨会，其中实验室的成员提出中间数据，并收到来自其他实验室成员和受邀教师的关键建议。这些智力资源与医学主席提供的支持该项目的财政资源相结合，将使PI能够在培训期结束时发展成为一名独立的研究者。