Defining the role of Pou6f1 in cardiac morphogenesis

定义 Pou6f1 在心脏形态发生中的作用

• 批准号: 9169706
• 负责人: NIKHIL Vilas MUNSHI
• 金额: $ 8.1万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9169706
• 关键词: Address; Biological Models; Cardiac; Cardiomyopathies; Cations; Clinical; Congenital Abnormality; Coupled; Data; Defect; Diagnostic; Disease; Dominant-Negative Mutation; Embryo; FDA approved; Failure; Female; Genetic Predisposition to Disease; Goals; Heart Abnormalities; Heart Atrium; Incidence; Knowledge; Live Birth; LoxP-flanked allele; Molecular; Morphogenesis; Mus; Mutation; Newborn Infant; Operative Surgical Procedures; Orthologous Gene; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Process; Research; Role; Structure; Testing; Tissues; Transcriptional Regulation; Ventricular septum; Zebrafish; cardiogenesis; congenital heart disorder; design; drug development; follow-up; gain of function; homeodomain; improved outcome; innovation; insight; male; molecular diagnostics; novel; outcome forecast; overexpression; programs; septal defect; stem; therapeutic target; transcription factor

Defining the role of Pou6f1 in cardiac morphogenesis PROJECT SUMMARY Congenital heart disease (CHD) is the leading cause of birth defects and continues to carry a poor long-term prognosis despite marked improvements in contemporary management. This failure stems from severely lim- ited diagnostic capabilities coupled with a complete inability to modify the underlying disease process. Alt- hough the transcriptional pathways responsible for heart development have been well-characterized, new regulators of the established circuitry are urgently needed to identify novel CHD candidate loci and illuminate potential therapeutic targets. The long-term goal of this research program is to understand transcriptional con- trol of cardiac lineage specification using atrioventricular canal (AVC) differentiation as a model system. The objective of this proposal is to characterize a recently identified upstream regulator of AVC specification. Our central hypothesis is that Pou6f1 regulates cardiac structure and function. To test this hypothesis, we propose the following specific aims: 1) Analyze cardiac phenotypes resulting from Pou6f1 over-expression and 2) De- termine the impact of Pou6f1 deletion on cardiac function. Our preliminary data indicate that cardiac-specific over-expression of dominant-negative Pou6f1 perturbs AVC morphogenesis and results in embryonic lethality. In Aim 1, we will examine the consequences of Pou6f1 gain-of-function during heart development by utilizing two mouse lines for tissue-specific Pou6f1 over-expression that we have generated in our lab. Additional pre- liminary results show that global Pou6f1 deletion causes male-specific embryonic lethality and cardiomyopathy in surviving females. In Aim 2, we will evaluate the functional consequences of global and cardiac-specific Pou6f1 deletion using a floxed allele that we have previously obtained. Our approach is innovative because it will challenge and expand the existing paradigm for AVC morphogenesis, a critical step for proper formation of the atrial septum, ventricular septum, and AV valves. This project is significant, therefore, because it will impli- cate an entirely new transcriptional pathway in AVC specification and cardiac morphogenesis. Taken togeth- er, the expected benefits from the proposed studies are to establish a role for Pou6f1 during cardiac morpho- genesis and to obtain key preliminary data for a competitive R01 submission. We anticipate that subsequent follow-up studies will provide a more informed mechanistic understanding of AVC morphogenesis. In turn, such insights promise to expand the list of candidate loci and provide a platform for the rational design of novel treatments for AVSDs.

确定Pou6f1在心脏形态发生中的作用