Establishing Genotype-to-Phenotype Relationships Between Alzheimer’s Related BIN1 Variants

建立阿尔茨海默病相关 BIN1 变异之间的基因型与表型关系

• 批准号: 10525652
• 负责人: DAVID A BRAFMAN
• 金额: $ 43.18万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525652
• 关键词: 3-Dimensional; AD transgenic mice; Abeta synthesis; Adaptor Signaling Protein; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Apoptosis; Autopsy; Biomedical Engineering; Brain; Calcium; Cell Line; Cells; Coculture Techniques; Complex; Data; Development; Disease; Disease Progression; Disease model; Endocytosis; Engineering; Ensure; Future; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genome engineering; Genotype; Gold; Homeostasis; Human; Human Engineering; Individual; Inflammation; Inflammatory; Investigation; Karyotype; Knock-out; Late Onset Alzheimer Disease; Link; Mediating; Methods; Modeling; Neuraxis; Neurodegenerative Disorders; Onset of illness; Pathology; Pathway interactions; Phenotype; Probability; Reporter; Reporting; Research; Resources; Risk; Risk Factors; Series; Signal Pathway; Signaling Protein; System; Testing; Therapeutic Intervention; Variant; amyloid precursor protein processing; base; base editing; cell growth; design; familial Alzheimer disease; gain of function; gene regulatory network; genetic risk factor; genome editing; genome wide association study; induced pluripotent stem cell; insight; knock-down; loss of function; molecular targeted therapies; mouse model; non-demented; overexpression; pluripotency; relating to nervous system; stem cell model; stem cells; synaptogenesis; tau Proteins; tau phosphorylation; transcriptome sequencing; tumor; uptake

PROJECT SUMMARY ABSTRACT Genome-wide association studies (GWAS) have identified several risk factors associated with altered probability of late onset Alzheimer’s disease (LOAD). In this regard, variation in bridging integrator 1 (BIN1) have been identified as being strongly associated with increased risk of AD. To that end, several preliminary studies have suggested that BIN1 not only modulates amyloid and tau pathology but also modulates various inflammatory and cell homeostatic pathways. Nonetheless, the mechanistic links between BIN1 and AD remain poorly defined. Moreover, there is a paucity of research examining the effects of BIN 1 variation on the manifestation or augmentation of AD-related phenotypes. In this proposal, we will use our collective expertise in stem cell bioengineering, neurodegenerative disease modeling, and genome engineering to investigate the relationship between specific BIN 1 variants and AD risk. In the first aim, we will using our highly efficient gene editing approach to introduce BIN1 variants into isogenic hiPSCs from healthy non-demented control (NDC) and AD patients. In the second aim, we will employ isogenic hiPSC lines in a 3-D co-culture model to test the hypothesis that these BIN variants exert their risk-modifying effects through (i) modulation of amyloid precursor protein (APP) processing and Aβ secretion and (ii) alteration in tau hyperphosphorylation and internalization. In addition, we will use RNA-seq analysis to identify signaling pathways, gene regulatory networks, and transcriptional targets that are independently influenced by the presence of BIN variation and disease status. In addition, through the use of BIN1 knockout hiPSCs we will be able to determine if these BIN1 variants induce their effects occur through gain- or loss-of-function mechanisms. Overall, a more thorough understanding of the mechanisms by which variation in BIN1 contributes to the likelihood of AD onset will have a significant impact on the design of therapeutic interventions.

项目总结摘要 全基因组关联研究已经确定了几个与概率改变相关的风险因素。 迟发性阿尔茨海默病(LOAD)。在这一点上，桥接积分器1(BIN1)中变异已经被 被认为与AD风险增加密切相关。为此，几项初步研究已经 提示BIN1不仅调节淀粉样蛋白和tau蛋白的病理改变，而且还调节各种炎症反应 和细胞内环境平衡途径。尽管如此，BIN1和AD之间的机械联系仍然没有明确的定义。 此外，很少有研究考察BIN-1变异对临床表现或 AD相关表型的增强。在这项提案中，我们将利用我们在干细胞方面的集体专业知识 生物工程、神经退行性疾病建模和基因组工程来研究它们之间的关系 特定的BIN1变异与AD风险之间的关系。在第一个目标中，我们将使用我们的高效基因编辑 将BIN1变异体导入健康非痴呆对照(NDC)和阿尔茨海默病(AD)等基因HiPSC的方法 病人。在第二个目标中，我们将在三维共培养模型中使用等基因的HiPSC系来检验这一假设 这些BIN变异体通过(I)调节淀粉样前体蛋白发挥其风险调节作用 (2)tau蛋白过度磷酸化和内化的变化。此外, 我们将使用rna-seq分析来确定信号通路、基因调控网络和转录。 受BIN变异和疾病状态独立影响的目标。此外, 通过使用BIN1基因敲除的HiPSCs，我们将能够确定这些BIN1变体是否会导致它们的影响 通过功能增益或功能损耗机制发生。总体而言，对这些机制有了更深入的了解 BIN1的变异对AD发病的可能性将对设计产生重大影响 治疗干预措施。