权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Single-cell multi-region dissection of AD-pathogen interactions for HSV-1 and CMV

HSV-1 和 CMV AD 病原体相互作用的单细胞多区域解剖

基本信息

批准号：
10607814
负责人：
Manolis Kellis
金额：
$ 78.61万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
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：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607814
关键词：
3-Dimensional Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid beta-Protein Atlases Autopsy Biological Assay Blood Vessels Brain Brain region COVID-19 pandemic CRISPR interference Cell Communication Cell Survival Cells Central Nervous System Coculture Techniques Complex Computing Methodologies Cytomegalovirus Cytomegalovirus Infections Data Data Set Dementia Development Disease Disease Progression Dissection Environmental Impact Etiology Family Foundations Gene Expression Profile Gene Expression Profiling Gene Expression Regulation Genes Genetic Genetic Risk Genetic Transcription Goals Healthcare Herpesvirus 1 Hippocampus Human Immune Immune response Impaired cognition Individual Infection Intervention Joints Life Link Maps Mediating Memory Loss Messenger RNA Microglia Modeling Molecular Molecular Mechanisms of Action Mus Neurodegenerative Disorders Neurons Organoids Pathogenicity Pathologic Pathway interactions Phenotype Post-Translational Protein Processing Regulatory Element Research Resolution Resources Role Sampling Severities Simplexvirus Testing Transcription Alteration Validation Virus abeta deposition antimicrobial peptide base brain cell care burden causal variant cell type cerebrovascular data integration frontal lobe genetic risk factor induced pluripotent stem cell neuroinflammation novel therapeutics pathogen personalized medicine personalized therapeutic protein expression risk variant sex single nucleus RNA-sequencing single-cell RNA sequencing small molecule therapeutics

项目摘要

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder that leads to dramatic effects on the affected individuals and their families. While the characterization of the genetic contribution to AD and underlying molecular mechanisms has advanced the understanding of the disease in recent years, studies have failed to find definitive mechanisms that account for disease progression. The influence of pathogens on AD potentially mediates an environmental impact on the established genetic contributions to AD. Here, we directly dissect the contribution of pathogen-related effects down to the cell-type-specific molecular basis by systematic profiling, computational integration, and experimental validation of the transcriptional signatures across individuals, brain regions, and cell types. In Aim 1, we use scRNA-seq in human, mouse, and human iPSC brain organoid samples of AD that are infected with Herpes Simplex Virus 1 or Cytomegalovirus (HSV-1/CMV) to generate millions of single- cell (sc) level maps with the end goal of a transcriptional atlas. In Aim 2, we analyze the resulting datasets and underlying molecular mechanisms, enabling us to discover and converge genes, pathways, cell types, and brain regions to functional and causal mechanisms that drive pathogen-related alterations. In Aim 3, we use our well-established iPSC model to test our predicted mechanisms with both high-throughput and cell-type specific assays. The resulting datasets, computational predictions, and experimentally-supported mechanisms will shed light on the pathogen-related influences on AD pathology and will help deepen our understanding of the disease in general as we develop more personalized therapeutic approaches to treating AD.

摘要阿尔茨海默病(AD)是一种神经退行性疾病，会对患者产生显著影响个人和他们的家人。虽然对阿尔茨海默病的遗传贡献的表征和潜在的近年来，分子机制促进了人们对该病的理解，但研究未能找出疾病进展的确切机制。病原体对阿尔茨海默病的潜在影响对已确定的阿尔茨海默病遗传贡献的环境影响起中介作用。在这里，我们直接剖析通过系统分析病原体相关效应对特定细胞类型的分子基础的贡献，跨个体、大脑的转录签名的计算集成和实验验证区域和单元格类型。在目标1中，我们在人、小鼠和人ipsc脑有机体样本中使用scRNA-seq。感染单纯疱疹病毒1型或巨细胞病毒(HSV-1/CMV)的AD可产生数百万单核细胞- 细胞(Sc)水平与转录图谱的最终目标相对应。在目标2中，我们分析得到的数据集，并潜在的分子机制，使我们能够发现和融合基因、途径、细胞类型和大脑区域与驱动病原体相关改变的功能和因果机制有关。在目标3中，我们使用我们完善的IPSC模型，用高通量和细胞类型来测试我们预测的机制特定的化验。得到的数据集、计算预测和实验支持的机制将有助于阐明病原体对AD病理的影响，并有助于加深我们对随着我们开发出更个性化的治疗方法来治疗阿尔茨海默病，这种疾病总体上也是如此。