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

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

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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.

项目摘要摘要全基因组关联研究（GWAS）已经确定了与概率改变相关的几种风险因素晚期发病的阿尔茨海默氏病（负载）。在这方面，桥接积分器1（BIN1）的变化已经被确定为与AD风险增加密切相关。为此，一些初步研究已经建议BIN1不仅调节淀粉样蛋白和TAU病理，而且调节各种炎症和细胞稳态途径。尽管如此，BIN1和AD之间的机械联系仍然很差。此外，研究bin 1变化对表现形式的影响或与广告相关表型的增强。在此提案中，我们将使用干细胞中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，以研究这种关系在特定的bin 1变体和AD风险之间。在第一个目标中，我们将使用高效的基因编辑将BIN1变体从健康的非痴呆对照（NDC）和AD中引入bin1变体的方法患者。在第二个目标中，我们将在3-D共培养模型中采用Isenic HIPSC线来检验假设这些bin变体通过（i）调节淀粉样前体蛋白会发挥其风险改善效果（APP）加工和Aβ分泌以及（ii）Tau高磷酸化和内在化的改变。此外，我们将使用RNA-seq分析来识别信号通路，基因调节网络和转录受垃圾箱变异和疾病状态的独立影响的靶标。此外，通过使用BIN1敲除hipscs，我们将能够确定这些BIN1变体是否诱导其效果通过获得或功能丧失的机制发生。总体而言，对机制有更透彻的理解 BIN1的变化有助于AD发作的可能性，将对设计产生重大影响治疗干预措施。