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

• 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
• 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' s Disease; Alzheimer' 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

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.

摘要 唐氏综合症是由21号染色体(HSA21)上的一组基因的三倍体引起的。具有以下特征的个人 DS均表现为一定程度的早发性阿尔茨海默病。最近的研究表明 除APP外，HSA21上基因的三倍复制导致了β-淀粉样蛋白(Abeta)加工的中断 在老鼠身上。是否在人类DS细胞中观察到类似的病理机制，以及 HSA21基因是造成这种干扰的原因，目前尚不清楚。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将允许敲除 一个HSA21拷贝，而其他两个拷贝保持不变。使用这种方法，我们可以系统地 确定HSA21基因的子集最有可能对改变的Abeta过程做出贡献。身份识别 HSA21基因的子集对DS中的AD负有最大的责任，这不仅对理解病理 这不仅有助于研究治疗这种疾病的机制，还有助于设计治疗这种疾病的适当疗法。