Investigating Genomic Instability and Loss of the Y Chromosome in Alzheimer’s Disease

研究阿尔茨海默病中的基因组不稳定性和 Y 染色体丢失

基本信息

批准号：
10740136
负责人：
HOLLY N CUKIER
金额：
$ 42.21万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740136
关键词：
Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s Disease Pathway Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid beta-Protein Biological Blood Brain CRISPR/Cas technology Candidate Disease Gene Cell Cycle Regulation Cell Line Cell Survival Cell physiology Cells DNA Damage Data Data Set Disease Endosomes Event Functional disorder Gene Expression Gene Expression Profile Genes Genetic Genetic Markers Genomic Instability Genomics Growth Guide RNA Immune In Vitro Individual Measures Memory Microglia Mitotic Molecular Morphology Neurofibrillary Tangles Neurologic Neurons Outcome Pathogenesis Pathogenicity Pathway interactions Patients Phagocytosis Phenotype Play Population Production Proteins Research Risk Role Sampling Universities Vertebral column Whole Blood Woman Work Y Chromosome abeta accumulation cell type chromosome X loss chromosome Y loss clinical phenotype cohort cytokine data harmonization differential expression disorder subtype experience experimental study genetic variant genome editing genome wide association study genomic biomarker hazard hyperphosphorylated tau imaging biomarker immune function immune system function in vivo induced pluripotent stem cell male mosaic loss neuroimaging neuron loss novel peripheral blood religious order study response sample collection senescence single-cell RNA sequencing stem cell model stem cells tau Proteins trafficking transcriptomics

项目摘要

PROJECT SUMMARY Since the early 90's, genetic factors have been shown to play a formidable role in contributing to Alzheimer's Disease (AD) risk. More recently, mosaic loss of the Y chromosome (LOY) has emerged as a novel risk biomarker for AD, and was confirmed by our own study to confer between a 1.63 to 2 fold increased hazard for AD diagnosis. LOY is a somatic event that occurs in males as they age. While the underlying biological mechanism that drives this risk remains unknown, genome wide association studies (GWAS) of LOY outcomes identified ~156 loci that contain genes involved in cell cycle regulation, mitotic pathways, and DNA damage response. The discovered genomic variants also predict X chromosome loss in women, suggesting that LOY is a marker of genomic instability in males that precedes the AD clinical phenotype. Typical AD pathology includes the abnormal production and accumulation of amyloid beta and tau proteins, which ultimately leads to plaques and neurofibrilary tangles, neuronal death, and loss of brain cortical volume. Bolstered by both genetic and molecular studies, the clearance of abnormal proteins by microglia has emerged as an important disease mechanism; immune system function is now thought to play a critical role in AD. In this project, we will investigate the relationship between LOY and AD pathogenesis. We hypothesize that in the context of Alzheimer's Disease, LOY in males is a marker of acquired genomic instability increasing risk of AD through a neuronal or glial senescence phenotype. We will examine this hypothesis through a unique fusion of population-level analyses and molecular experiments to 1) examine whole-blood transcriptomic changes in LOY+ individuals; and 2) determine differences in immune cellular function using induced pluripotent stem cell lines (iPSCs) with LOY.

项目概要自 20 世纪 90 年代初以来，遗传因素已被证明在导致阿尔茨海默病方面发挥着巨大作用疾病 (AD) 风险。最近，Y 染色体嵌合体丢失 (LOY) 已成为一种新的风险 AD 的生物标志物，经我们自己的研究证实，AD 的风险增加 1.63 至 2 倍 AD诊断。 LOY是男性随着年龄增长而发生的躯体事件。虽然潜在的生物驱动这种风险的机制仍然未知，LOY 结果的全基因组关联研究 (GWAS) 鉴定出约 156 个基因座，其中包含参与细胞周期调节、有丝分裂途径和 DNA 损伤的基因回复。发现的基因组变异还预测女性 X 染色体丢失，表明 LOY AD 临床表型之前男性基因组不稳定的标志。典型的 AD 病理包括β淀粉样蛋白和tau蛋白的异常产生和积累，最终导致斑块和神经原纤维缠结、神经元死亡和脑皮质体积损失。受到双方基因的支持和分子研究，小胶质细胞清除异常蛋白已成为一种重要的疾病机制;现在认为免疫系统功能在 AD 中发挥着关键作用。在这个项目中，我们将探讨LOY与AD发病机制之间的关系。我们假设在这样的背景下阿尔茨海默氏病，男性中的 LOY 是获得性基因组不稳定性的标志，通过以下方式增加患 AD 的风险神经元或神经胶质衰老表型。我们将通过独特的融合来检验这个假设群体水平分析和分子实验 1) 检查全血转录组变化 LOY+ 个人； 2) 使用诱导多能干细胞确定免疫细胞功能的差异具有 LOY 的细胞系（iPSC）。