A molecular pathway controlling cardiomyocyte specification.

控制心肌细胞规格的分子途径。

• 批准号: 8219248
• 负责人: Todd R Evans
• 金额: $ 42.25万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8219248
• 关键词: Alleles; Animal Model; Binding; Biological Models; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell model; Cessation of life; Clinical; Congenital Abnormality; Development; Embryo; Embryonic Development; Failure; Future; GATA5 Transcription Factor; Gene Targeting; Generations; Genes; Genetic; Genome; Goals; Growth; Heart; Heart Diseases; Heart failure; In Vitro; Live Birth; Maps; Mediating; Mesoderm; Modeling; Molecular; Morphogenesis; Mus; Myocardial; Myocardium; Newborn Infant; Pathway interactions; Persons; Pluripotent Stem Cells; Population; Pre-Clinical Model; Process; Production; Sister; Societies; Specific qualifier value; Specificity; System; Testing; Tissues; Translations; United States; Zebrafish; cardiogenesis; embryonic stem cell; genome-wide; killings; loss of function; network models; novel; progenitor; programs; regenerative; tool; transcription factor

DESCRIPTION (provided by applicant): Heart disease is the major cause of death in the United States. A loss of myocardial function, or failure to replace damaged myocardium, underlies the tremendous burden on our society caused by cardiovascular disease, killing an average of 1 person every 39 seconds. Likewise, cardiovascular developmental anomalies are the most common congenital defects in newborns, presenting in nearly 1% of live births. Many of the transcription factors controlling cardiogenesis are now known and comprise a molecular network essential for normal heart growth, morphogenesis, and function. However, the initial step of specifying cardiac progenitors from uncommitted early embryonic mesoderm is poorly understood. Progress in understanding this process could be exploited to develop regenerative strategies for treating cardiovascular disease, including heart failure. We have discovered a genetic pathway that is both necessary and sufficient during embryonic development for the generation of cardiomyocytes. A central component of this pathway is the Gata5 transcription factor, which has been relatively overlooked with respect to its function in cardiogenesis. We found that expression of Gata5, during a specific developmental window, is sufficient to efficiently generate cardiomyocytes from a mouse pluripotent stem cell progenitor population. We also showed that gata5 is required during embryogenesis, along with its sister gene gata6, for the normal specification of zebrafish cardiomyocytes. Thus, we established high-throughput model systems to generate or eliminate the production of cardiomyocytes. We developed tools to discover the genetic pathways controlled by gata5 at both the transcriptional and translational levels. We developed new conditional strategies to control the pathway with spatial and temporal specificity. We have assembled a team with expertise in genome-wide molecular network modeling, and we can evaluate the function of candidate network components with high throughput. We propose to fully interrogate at the whole genome level the essential downstream molecular pathway(s) that promote or restrict the generation of cardiomyocytes, and to discover novel regulators of cardiomyocyte fate. A complete understanding of these programs will reveal new cellular or pharmacological strategies for restoring damaged cardiac tissue caused by cardiovascular disease. Toward this goal, Aims are proposed to: 1) Discover the genetic network sufficient to mediate cardiomyocyte specification in a mammalian embryonic stem cell model. 2) Identify the regulatory network necessary to mediate cardiomyocyte specification in a vertebrate embryo, using a complementary zebrafish animal model, and 3) Define temporal- specific components of the cardiomyocyte specification program using conditional loss-of-function strategies in the zebrafish model. Most importantly, we will identify and test the function of previously unknown components of the cardiomyocyte specification network. PUBLIC HEALTH RELEVANCE: Heart disease is the major cause of death in the United States, often due to death or failure in function of cardiomyocytes. We discovered a genetic pathway that is both necessary and sufficient during embryonic development for the generation of cardiomyocytes, and have developed the tools and expertise to interrogate at the whole genome level the essential downstream molecular pathways. A complete understanding of these programs will reveal new cellular or pharmacological strategies for restoring damaged cardiac tissue caused by cardiovascular disease.

描述（由申请人提供）：心脏病是美国的主要死亡原因。心肌功能丧失或无法更换受损心肌是心血管疾病给我们社会造成的巨大负担，平均每 39 秒就有 1 人死亡。同样，心血管发育异常是新生儿最常见的先天性缺陷，近 1% 的活产婴儿出现这种情况。现在已知许多控制心脏发生的转录因子，它们包含正常心脏生长、形态发生和功能所必需的分子网络。然而，从未定型的早期胚胎中胚层中鉴定心脏祖细胞的第一步却知之甚少。理解这一过程的进展可用于开发治疗心血管疾病（包括心力衰竭）的再生策略。我们发现了在胚胎发育过程中对于心肌细胞的产生既必要又充分的遗传途径。该通路的核心成分是 Gata5 转录因子，但其在心脏发生中的功能相对被忽视。我们发现，在特定的发育窗口期间，Gata5 的表达足以有效地从小鼠多能干细胞祖细胞群中产生心肌细胞。我们还表明，在胚胎发生过程中，gata5 及其姐妹基因 gata6 是斑马鱼心肌细胞正常规格所必需的。因此，我们建立了高通量模型系统来产生或消除心肌细胞的产生。我们开发了工具来发现 gata5 在转录和翻译水平上控制的遗传途径。我们开发了新的条件策略来控制具有空间和时间特异性的路径。我们组建了一支具有全基因组分子网络建模专业知识的团队，我们可以高通量评估候选网络组件的功能。我们建议在全基因组水平上全面探究促进或限制心肌细胞生成的重要下游分子途径，并发现心肌细胞命运的新调节因子。对这些程序的全面了解将揭示恢复心血管疾病引起的受损心脏组织的新细胞或药理学策略。为了实现这一目标，建议目标是：1）发现足以介导哺乳动物胚胎干细胞模型中心肌细胞规范的遗传网络。 2) 使用互补的斑马鱼动物模型确定介导脊椎动物胚胎中心肌细胞规格所需的调节网络，以及 3) 使用斑马鱼模型中的条件功能丧失策略定义心肌细胞规格程序的时间特异性组成部分。最重要的是，我们将识别和测试心肌细胞规范网络中以前未知的组件的功能。 公共卫生相关性：心脏病是美国的主要死亡原因，通常是由于心肌细胞死亡或功能衰竭所致。我们发现了在胚胎发育过程中对于心肌细胞的产生既必要又充分的遗传途径，并且开发了工具和专业知识来在全基因组水平上询问重要的下游分子途径。对这些程序的全面了解将揭示恢复心血管疾病引起的受损心脏组织的新细胞或药理学策略。