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口中普遍存在的出生缺陷 高达1000个活产中的10个。 许多独立的遗传基因座与Allres之间的相互作用。 先天性心脏缺陷的多基因性质，必须识别新基因 监管合作伙伴可能会在我们的实验室中发挥作用 最近确定的辅因子Akirin，该辅助因素是导致转录与染色质连接的 重塑机械以促进基因表达。 果蝇中的胚胎心脏的构图和形态发生 数据表明Akirin可能通过与之相互作用来调节昆虫的胚胎心脏发育 CHD4/染色质改建机械的NURD家族。 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相互作用在心脏发展过程中的作用，我们提出了两个 特定目的：1）结合遗传，生化和实时成像技术的组合，将确认您 在开发过程中Akirin/Nurd互动的重要性，2）我们将采用下一代 大量平行的RNA测序方法，以及ATAC-SEQ和常规染色质 免疫沉淀方法来确定心脏肌发生过程中阿基林的基因调节作用。 工作将提供关键数据，以了解Akirin在心脏形成过程中的作用，并提供 研究和/或预防先天性心脏缺陷原因的新途径。 至关重要的是，为了符合该地区奖励机制的目标，该项目将提供地下 研究人员在各种分子，遗传学，组织学，微观和微观方面的实践经验 生化技术将为生物医学研究的未来职业提供宝贵的技能。