INCLUDE19-Ancestral roles of histone-modifying genes in heart development and disease

INCLUDE19-组蛋白修饰基因在心脏发育和疾病中的祖先作用

• 批准号: 9898029
• 负责人: ZHE HAN
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-20 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898029
• 关键词: Address; Adult; Affect; Animal Model; Area; Basic Science; Biological Models; Candidate Disease Gene; Cardiac; Cardiac development; Chromosomes, Human, Pair 21; DNA Sequence Alteration; Data; Defect; Development; Disease model; Down Syndrome; Drosophila genus; Embryo; Embryonic Heart; Future; Gene Combinations; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Grant; Heart; Heart Abnormalities; Heart Diseases; Histones; Human; Human Chromosomes; Maps; Methods; Modeling; Molecular; Mus; Parents; Patients; Phenotype; Pilot Projects; Prevention approach; Research; Role; Sampling Studies; Series; Severities; Stem cells; Structure; Systems Analysis; Testing; Therapeutic; Time; Tissue Sample; Transcriptional Activation; Transgenic Organisms; Trisomy; base; cardiogenesis; causal variant; comparative; congenital heart disorder; fly; gene function; genetic linkage; heart cell; insight; mortality; mouse model; novel; overexpression; parent grant; precision medicine; response; tool; transcriptome sequencing; transcriptomics; transgene expression

Abstract This application is being submitted in response to NOT-OD-19-071. Here, we propose to add Down Syndrome (DS) research objectives to our parent R01 grant, originally not focused on DS. Our new DS-focused objectives are basic science studies addressing Component 1 of the INCLUDE project in two areas. First, we will develop a novel model system to identify and study genes involved in CHD in DS patients. Second, we will perform transcriptomic profiling studies using this new model organism for CHD in DS patients. Approximately half of DS patients have CHD, but the responsible genes are not known. This poses a challenge to understanding the molecular mechanism underlying DS-CHD. Using mouse DS models, our collaborator was able to map the DS-CHD causal genes within two small loci (or linkage groups) together containing 18 genes, and furher demonstrated that CHD requires a combination of genes from both loci. However, systematic testing of all 72 possible two-gene combinations in the mouse model would be prohibitively expensive. Because early heart development is controlled by highly conserved genetic networks from flies to humans, a Drosophila- based model testing and analysis system is an ideal approach to identification of the specific gene combinations responsible for DS-CHD. We thus propose to generate and characterize Drosophila models of CHD in DS patients based on our collaborator’s discoveries and our pilot studies. We will also perform transcriptomic profiling on fly defective hearts resulting from co-expression of causal gene combination(s), and compare this data to results from mouse models and DS patient tissue sample studies. Successful completion of this supplemental project will lead to the identification of the specific gene combination causing CHD in DS patients. This is essential for understanding the molecular mechanism underlying DS-CHD and future development of precision medicine-based therapeutic approaches to prevention and treatment.

摘要 本申请是根据NOT-OD-19-071提交的。在这里，我们建议添加Down 综合征（DS）的研究目标，以我们的父母R 01赠款，原来不集中在DS。我们的新 以DS为重点的目标是针对INCLUDE项目第1部分的基础科学研究 在两个方面。首先，我们将开发一个新的模型系统来识别和研究参与基因。 DS患者的CHD。其次，我们将使用这种新模型进行转录组学分析研究 DS患者中CHD的微生物。大约一半的DS患者患有CHD，但负责的 基因未知。这对理解潜在的分子机制提出了挑战 DS-CHD。使用小鼠DS模型，我们的合作者能够绘制DS-CHD致病基因 在两个小位点（或连锁群）内，共包含18个基因，进一步证明， CHD需要来自两个基因座的基因的组合。然而，对所有72种可能的 小鼠模型中的两个基因组合将是极其昂贵的。因为早心 发育是由高度保守的遗传网络控制的，从果蝇到人类， 基于模型的检测分析系统是一种理想的特异性基因识别方法 导致DS-CHD的组合。因此，我们建议产生和表征果蝇 根据我们合作者的发现和我们的初步研究，我们将 还对由致病基因的共表达引起的果蝇缺陷心脏进行转录组学分析， 基因组合，并将该数据与小鼠模型和DS患者组织的结果进行比较 样本研究。成功完成这一补充项目将导致确定 导致DS患者CHD的特异性基因组合。这对于理解 DS-CHD的分子机制和基于精准医学的未来发展 预防和治疗的治疗方法。