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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

项目概要摘要全基因组关联研究（GWAS）已经确定了与概率相关的几个风险因素在这方面，桥接积分蛋白 1 (BIN1) 的变异已成为晚发性阿尔茨海默病 (LOAD) 的重要原因。为此，一些初步研究已确定其与 AD 风险增加密切相关。表明 BIN1 不仅调节淀粉样蛋白和 tau 蛋白病理学，还调节各种炎症然而，BIN1 和 AD 之间的机制联系仍然不明确。此外，很少有研究检验 BIN 1 变异对表现或症状的影响。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、神经退行性疾病模型和基因组工程来研究这种关系特定 BIN 1 变异与 AD 风险之间的关系第一个目标是，我们将使用我们的高效基因编辑。将 BIN1 变体引入来自健康非痴呆对照 (NDC) 和 AD 的同基因 hiPSC 的方法在第二个目标中，我们将在 3D 共培养模型中采用同基因 hiPSC 系来检验该假设。这些 BIN 变体通过 (i) 调节淀粉样前体蛋白发挥其风险调节作用 (APP) 加工和 Aβ 分泌以及 (ii) tau 过度磷酸化和内化的改变。我们将使用 RNA-seq 分析来识别信号通路、基因调控网络和转录此外，受 BIN 变异和疾病状态独立影响的目标。通过使用 BIN1 敲除 hiPSC，我们将能够确定这些 BIN1 变体是否会诱导其作用总体而言，通过功能获得或丧失机制发生。 BIN1 的变化会增加 AD 发生的可能性，这将对设计产生重大影响的治疗干预措施。