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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的此申请是针对 NOT-OD-19-071 提交的，我们建议在此添加 Down。综合症（DS）研究目标是我们的母公司R01资助的，最初并不专注于我们新的DS。 DS 重点目标是针对 INCLUDE 项目第 1 部分的基础科学研究首先，我们将开发一个新的模型系统来识别和研究涉及的基因。其次，我们将使用这种新模型进行转录组学分析研究。 DS 患者中大约有一半的 DS 患者患有 CHD，但其发病原因是。基因尚不清楚，这对理解潜在的分子机制提出了挑战。使用小鼠 DS 模型，我们的合作者能够绘制 DS-CHD 致病基因图谱。在两个包含 18 个基因的小位点（或连锁群）内，并进一步证明 CHD 需要两个基因座的基因组合，但需要对所有 72 个可能的基因进行系统测试。小鼠模型中的两个基因组合将非常昂贵，因为早期心脏。果蝇的发育是由从果蝇到人类的高度保守的遗传网络控制的基于模型的测试和分析系统是识别特定基因的理想方法因此，我们建议生成并表征果蝇。我们将根据我们合作者的发现和试点研究，建立 DS 患者的 CHD 模型。还对因因果共表达而导致的果蝇缺陷心脏进行转录组分析基因组合，并将该数据与小鼠模型和 DS 患者组织的结果进行比较成功完成该补充项目将导致确定 DS 患者中引起 CHD 的特定基因组合对于了解 DS 患者的 CHD 至关重要。 DS-CHD的分子机制及精准医疗的未来发展预防和治疗的治疗方法。