Deciphering HSA21 genes associated with Alzheimers disease in Down Syndrome

破译与唐氏综合症中阿尔茨海默病相关的 HSA21 基因

基本信息

批准号：
10120793
负责人：
VOLNEY L SHEEN
金额：
$ 28.19万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2023-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10120793
关键词：
Administrative Supplement Age-Years Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-42 Amyloid beta-Protein Brain CRISPR/Cas technology Candidate Disease Gene Cell Culture Techniques Cell Line Cells Chromosome 21 Clustered Regularly Interspaced Short Palindromic Repeats Code Cognition Complement Complex Development Disease Down Syndrome Epigenetic Process Funding Gene Cluster Gene Proteins Genes Genetic Genetic Diseases Grant Guidelines Human Indiana Individual Live Birth Longevity Messenger RNA Methods MicroRNAs Modeling Mus Mutation Neurofibrillary Tangles Neurologic Neurons Open Reading Frames PPBP gene Pathogenesis Pathologic Peptides Phenotype Pilot Projects Presenile Alzheimer Dementia Proteins Resource Development Subgroup Tc1 mouse Techniques Testing Time United States National Institutes of Health V717F Work abeta accumulation base clinical development experimental study falls genetic risk factor human model induced pluripotent stem cell interest knock-down mouse model novel novel strategies trait

项目摘要

Summary Down syndrome arises from the triplication of a subset of genes on chromosome 21 (HSA21). Individuals with DS uniformly demonstrate some degree early onset Alzheimers disease. Recent studies have suggested triplication of genes on HSA21, other than APP, contribute to the disruption of beta amyloid (Abeta) processing in mice. Whether similar pathological mechanisms are observed in human DS cells, as well as what subset of HSA21 genes are responsible for this disruption, remain unknown. We have developed a simple but novel approach using CRISPR gene editing techniques and DS cell culture models which will allow for knockdown of a single HSA21 copy, while leaving the other two copies intact. With this approach, we can systematically identify the subset of HSA21 genes most likely to contribute to the altered Abeta processing. Identification of the subset of HSA21 genes most responsible for AD in DS is not only critical for understanding pathological mechanisms, but also for devising appropriate therapies for treatment of this disorder.

概括唐氏综合症是由 21 号染色体 (HSA21) 上的一个基因子集的三倍体引起的。个人有 DS 一致证明了某种程度的早发性阿尔茨海默病。最近的研究表明除了 APP 之外，HSA21 上基因的三倍体也会导致 β 淀粉样蛋白 (Abeta) 加工的破坏在小鼠中。人类 DS 细胞中是否观察到类似的病理机制，以及属于哪些子集 HSA21 基因是造成这种破坏的原因，目前仍不清楚。我们开发了一种简单但新颖的使用 CRISPR 基因编辑技术和 DS 细胞培养模型的方法，这将允许敲低单个 HSA21 副本，同时保持其他两个副本完好无损。通过这种方法，我们可以系统地确定最有可能导致 Abeta 处理改变的 HSA21 基因子集。鉴定对 DS 中的 AD 最有影响的 HSA21 基因子集不仅对于理解病理学至关重要机制，而且还用于设计治疗这种疾病的适当疗法。