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Investigating the Functional Impact of AD Risk Genes on Neuro-Vascular Interactions

研究 AD 风险基因对神经血管相互作用的功能影响

基本信息

批准号：
10681808
负责人：
Oscar Harari
金额：
$ 12.18万
依托单位：
REGENERATIVE RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681808
关键词：
3-Dimensional ATAC-seq Address Alzheimer disease screening Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Architecture Autopsy Bioinformatics Biological Biological Models Biomedical Engineering Blood - brain barrier anatomy Blood Vessels Brain Brain Pathology Brain region CRISPR interference CRISPR-mediated transcriptional activation Candidate Disease Gene Cell Communication Cell Line Cell Nucleus Cell Survival Cell physiology Cells Cerebral Amyloid Angiopathy Cerebrovascular Circulation Cerebrovascular system Cerebrum Clustered Regularly Interspaced Short Palindromic Repeats Code Collaborations Collection Complex Coupling Data Data Set Dementia Deposition Development Disease Disease Progression Elements Endothelial Cells Endothelium Engineering Event Exhibits Gene Expression Genes Genetic Risk Genomics Goals Guide RNA Human Impairment Individual Inflammation Inflammatory Interdisciplinary Study Intervention Investigation Knock-in Knowledge Lead Libraries Ligands Light Link Maps Metabolic Diseases Methods Microvascular Dysfunction Modality Modeling Molecular Mus Nerve Degeneration Neurons Nuclear Organoids Outcome Pathologic Pathology Pathway interactions Perfusion Pericytes Phenotype Population Production RNA library Resources Risk Sampling Signal Transduction Smooth Muscle Myocytes System Testing Untranslated RNA Vascular Diseases Woman adeno-associated viral vector base brain endothelial cell cerebrovascular pathology cognitive change cognitive function combat comorbidity data sharing dementia risk endothelial stem cell functional genomics genetic testing genetic variant genome wide association study human stem cells in vivo induced pluripotent stem cell inflammatory marker member men mind control monolayer mouse model multidisciplinary neuropathology neurovascular polygenic risk score pre-clinical prime editing prime editor protein expression receptor risk variant screening sex single-cell RNA sequencing stem cell model synaptogenesis tau Proteins therapeutic development three-dimensional modeling transcriptome sequencing transcriptomics transgenic model of alzheimer disease translatome

项目摘要

PROJECT SUMMARY/ABSTRACT Cerebrovascular pathology is present throughout stages of Alzheimer’s Disease and is correlated with cognitive changes. There is strong evidence that vascular dysfunction is a significant driver of neuropathology. Our long- term objective is to understand the function of Alzheimer’s Disease-associated risk genes in vascular cells, their contribution to the development of cerebrovascular pathology and the opportunities to use this information in therapeutic development. There are over 27 Alzheimer’s Disease-associated risk (AD-risk) loci encompassing numerous genetic variants in non-coding and coding regions and hundreds of linked genes. Our overarching hypothesis is that a subset of AD-risk genes impairs vascular function, causing release of inflammatory factors, blood brain barrier (BBB) impairment, and reduced perfusion, thus contributing to neurodegeneration. To address this, we have assembled a multi-disciplinary team with a proven track record of collaboration, including with ADSP and ADGP members, who bring expertise in vascular pathology in dementia, endothelial cell (EC) signaling and EC functional testing, Alzheimer’s Disease genomics, single cell and nuclear transcriptomics, bioinformatics, CRISPR-based gene editing for large scale screening and AD mouse models for in-depth functional assessment in vivo. Notably, we will address differences in gene effects related to the important biological variables, sex and metabolic disease. Men and women differ in their genetic risk for Alzheimer’s Disease, with sex-specific polygenic risk scores providing better prediction of onset, progression, and pathology than pooled-sex scores. Over 80% of individuals with Alzheimer’s Disease have co-morbid metabolic disease, which exacerbates vascular pathology. We have identified the top 50 AD-risk SNPs and 600 AD-associated genes, and these will be targeted for induced pluripotent stem cell (iPSC)-derived endothelial cell (EC) screens by prime editing and CRISPR-based gene inhibition and activation approaches respectively. iPSC-based production of human ECs and mural cells in 2D and 3D models has been optimized and scaled to enable efficient functional testing of the impact of gene changes, including on neuro-vascular interactions in cerebral organoids. Discoveries made in these human cell systems will be validated by an in-depth investigation of gene expression changes in individual ECs and mural cells across a large collection of Alzheimer’s Disease brain samples using single nuclear sequencing. The EC translatome will also be obtained from mouse Alzheimer’s Disease models that incorporate sex and metabolic disease. These diverse datasets will be harmonized and integrated in order to map vascular phenotypes of AD-risk genes and identify critical molecular pathways that are targetable drivers of AD cerebrovascular pathology. These data will add to the breadth of knowledge being gathered by other groups to further elucidate underlying neuronal, glial, microglial, endothelial and mural cell-cell interactions that contribute in a substantial way to the complex architecture of Alzheimer Disease pathology. 1

项目摘要/摘要脑血管病变存在于阿尔茨海默病的各个阶段，并与认知相关改变。有强有力的证据表明，血管功能障碍是神经病理的重要驱动因素。我们的长- 学期目标是了解阿尔茨海默病相关风险基因在血管细胞中的功能，他们的对脑血管病理学发展的贡献和利用这些信息的机会治疗方面的发展。有超过27个阿尔茨海默病相关风险(AD-Risk)基因座包括非编码区和编码区的大量遗传变异和数百个连锁基因。我们最重要的是假说是AD风险基因的一个子集损害血管功能，导致炎症因子的释放，血脑屏障(BBB)受损，血流灌注减少，从而导致神经变性。至为了解决这一问题，我们组建了一个多学科团队，具有良好的协作记录，包括拥有ADSP和ADGP成员，他们带来了痴呆症血管病理、内皮细胞(EC)方面的专业知识信号和EC功能测试，阿尔茨海默病基因组学，单细胞和核转录组学，生物信息学，基于CRISPR的基因编辑用于大规模筛查和AD小鼠模型的深入研究活体功能评估。值得注意的是，我们将解决与重要的基因效应相关的差异生物变量、性和代谢性疾病。男性和女性患阿尔茨海默氏症的遗传风险不同疾病，性别特定的多基因风险评分可以更好地预测发病、进展和病理而不是共享性爱分数。超过80%的阿尔茨海默病患者患有共病代谢性疾病，这会加剧血管病变。我们已经确定了前50个AD风险SNP和600个AD相关SNP 基因，这些基因将被用于诱导多能干细胞(IPSC)来源的内皮细胞(EC)的筛查分别通过原始编辑和基于CRISPR的基因抑制和激活方法。基于IPSC的 2D和3D模型中的人体内皮细胞和壁细胞的生产已经过优化和缩放，以实现高效对基因变化的影响的功能测试，包括对大脑器官中神经-血管相互作用的影响。在这些人类细胞系统中的发现将通过对基因表达的深入研究来验证大量收集的阿尔茨海默病脑样本中单个内皮细胞和壁细胞的变化单核测序。EC翻译组也将从小鼠阿尔茨海默病模型中获得包括性和新陈代谢疾病。这些不同的数据集将按顺序进行协调和集成绘制AD危险基因的血管表型图并确定作为靶向驱动因素的关键分子通路阿尔茨海默病的脑血管病理学。这些数据将增加其他人收集的知识的广度进一步阐明潜在的神经元、胶质细胞、小胶质细胞、内皮细胞和壁细胞与细胞之间的相互作用对阿尔茨海默病病理的复杂结构做出了实质性的贡献。 1