Regulation of cardiac patterning via Akirin/NuRD Interactions

通过 Akirin/NuRD 相互作用调节心脏模式

• 批准号: 10514703
• 负责人: Anton Bryantsev
• 金额: $ 40.63万
• 依托单位: KENNESAW STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-05 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514703
• 关键词: ATAC-seq; Address; Affect; Alleles; Award; Biochemical; Biological Assay; Biomedical Research; Birth; CHD4 gene; Candidate Disease Gene; Cardiac; Cardiac development; Chromatin; Chromatin Remodeling Factor; Collaborations; Complex; Congenital Abnormality; Congenital Heart Defects; Data; Deacetylase; Defect; Destinations; Development; Developmental Gene; Disease; Drosophila genus; Drosophila melanogaster; Embryo; Embryonic Development; Embryonic Heart; Enhancers; Environment; Faculty; Family; Female; Fetal health; Funding; Future; Gene Expression; Genes; Genetic; Genetic Processes; Genetic Techniques; Goals; Halo Effects; Heart; Heart Abnormalities; Histologic; Histones; Human; Imaging Techniques; Incidence; Insecta; Institution; Laboratories; Laboratory Research; Learning; Live Birth; Mammals; Mentors; Methods; Microscopic; Molecular; Molecular Genetics; Morphogenesis; Muscle; Nature; Newborn Infant; Nuclear Protein; Nucleosomes; Pathway interactions; Pattern; Personal Satisfaction; Physiological; Play; Population; Prevention; Process; Proteins; Regulation; Regulator Genes; Research; Research Personnel; Role; STEM field; Structure; Students; Techniques; Time; Training; Transcript; Underrepresented Populations; United States National Institutes of Health; Universities; Vertebrates; Work; base; cardiogenesis; career; chromatin immunoprecipitation; chromatin remodeling; cofactor; congenital heart disorder; differential expression; experience; genomic locus; innovation; member; mutant; myogenesis; negative affect; next generation; novel; prevent; programs; skeletal; skills; success; transcription factor; transcriptome sequencing; undergraduate research; undergraduate student

Project Summary Congenital heart defects are the most prevalent birth defects in the human population, with an incident rate as high as 10 in 1000 live births. A significant number of these cases are termed sporadic, which are largely the result of interactions between a number of independent genetic loci and alleles. To aid in our understanding of the polygenic nature of congenital heart defects, it remains imperative to continue to identify new gene regulatory partners that may play a role in the process of embryonic heart patterning. Our laboratory has recently identified a cofactor, Akirin, that is responsible for interfacing transcription factor activity with chromatin remodeling machinery to facilitate gene expression. Importantly, Akirin appears to play a role in the proper patterning and morphogenesis of the embryonic heart in Drosophila melanogaster. Excitingly, our preliminary data suggests that Akirin likely regulates insect embryonic heart development through interactions with the CHD4/NuRD family of chromatin remodeling machinery. This mechanism of Akirin/NuRD interactions for expression of cardiac developmental gene pathways appears to be conserved from mammals to insects. To further determine the role of Akirin/NuRD interactions in the process of heart development, we propose two specific aims: 1) Using a combination of genetic, biochemical, and live imaging techniques, will confirm the importance of Akirin/NuRD interactions during development, and 2) We will employ both next-generation massively parallel RNA sequencing methods, as well as ATAC-seq and conventional chromatin immunoprecipitation methods to determine the gene regulatory role of Akirin during cardiac myogenesis. This work will provide key data for understanding the role of Akirin in the process of heart formation, and provide a new avenue for studying and/or preventing causes of congenital heart defects. Critically, in keeping with the goals of the AREA award mechanism, this project will give undergraduate researchers hands-on experience in a wide variety of molecular, genetic, histological, microscopic, and biochemical techniques, which will provide a valuable skill set for a future career in biomedical research.

项目摘要 先天性心脏缺陷是人类人口中最普遍的出生缺陷，发病率为 每1000名活产婴儿中有10名死亡。这些病例中有相当一部分被称为散发性病例，主要是在 这是许多独立的基因座和等位基因之间相互作用的结果。帮助我们理解 先天性心脏病的多基因性，继续鉴定新的基因仍然是当务之急。 可能在胚胎心脏形成过程中发挥作用的调节伙伴。本实验室 我最近艾德一种辅助因子Akirin，它负责将转录因子的活性与染色质连接起来 重塑机器以促进基因表达。重要的是，Akirin似乎在适当的 黑腹果蝇胚胎心脏的模式和形态发生。令人兴奋的是，我们的初步 数据表明Akirin很可能通过与昆虫胚胎心脏的相互作用来调节昆虫胚胎心脏的发育。 CHD 4/NuRD家族的染色质重塑机制。Akirin/NuRD相互作用的这种机制， 从哺乳动物到昆虫，心脏发育基因途径的表达似乎是保守的。 为了进一步确定Akirin/NuRD相互作用在心脏发育过程中的作用，我们提出了两个 具体目标：1）使用遗传，生物化学和活体成像技术的组合，将确认 Akirin/NuRD在开发过程中相互作用的重要性，以及2）我们将采用下一代 大规模并行RNA测序方法，以及ATAC-seq和常规染色质 免疫沉淀方法来确定Akirin在心肌发生过程中的基因调节作用。这 这项工作将为理解Akirin在心脏形成过程中的作用提供关键数据，并提供一个 研究和/或预防先天性心脏病原因的新途径。 重要的是，为了与区域奖励机制的目标保持一致，该项目将为本科生提供 研究人员在各种分子，遗传，组织学，显微镜， 生物化学技术，这将提供一个宝贵的技能，为未来的职业生涯在生物医学研究。