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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：
10216623
负责人：
Oscar Harari
金额：
$ 165.83万
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/10216623
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 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 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

项目总结/文摘