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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.

项目摘要