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Identification and functional analysis of novel human-specific small vessel disease proteins

新型人类特异性小血管疾病蛋白的鉴定和功能分析

基本信息

批准号：
9356592
负责人：
Michael M Wang
金额：
$ 15.75万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9356592
关键词：
Affect Alzheimer&apos s Disease Animal Model Atlases Blood Vessels Brain Brain Diseases CADASIL Cell Culture Techniques Cerebral small vessel disease Cerebrovascular Disorders Cerebrovascular system Cessation of life Comorbidity Cysteine Dementia Disease Disease model Elderly Exhibits Future Genetic Health High Prevalence Human Immunohistochemistry Impaired cognition Ischemic Stroke Knowledge Manuals Michigan Microvascular Dysfunction Mining Modeling Molecular Conformation Mouse Protein Mus Muscle Proteins Muscular Atrophy Mutation NOTCH3 gene Neurologic Parkinson Disease Pathogenesis Pathologic Pathology Patients Phenotype Play Population Pre-Clinical Model Property Protein Databases Proteins Proteome Public Health RANK protein Rattus Research Resources Role Severities Smooth Muscle Stroke Testing Tissue imaging Transgenic Mice Transgenic Organisms United States Universities Vascular Dementia Vascular Smooth Muscle Work cerebrovascular clinical development clinically relevant comparative experimental analysis experimental study human disease human imaging human tissue improved insight mouse model mutant nervous system disorder novel novel strategies pre-clinical premature protein expression screening success therapy development tissue resource

项目摘要

ABSTRACT Cerebral small vessel disease (SVD) is a common but untreatable condition identified over a half century ago. Affecting over half of the elderly in the United States, SVD leads to stroke and dementia and remains a significant public health concern. We study a genetic cause of SVD: CADASIL. CADASIL is the most common monogenic form of SVD and results from cysteine-altering mutations in the vascular smooth muscle protein NOTCH3. To understand mechanisms of SVD, mouse models of CADASIL have been generated with modest success. Though CADASIL models demonstrate accumulation of NOTCH3, they lack critical signs and pathological features of the disorder. For example, mutant NOTCH3 mice do not develop stroke or cognitive dysfunction, nor do they develop vascular smooth muscle loss and arterial thickening. The overall objective of this work is to gain insight regarding human CADASIL pathology that can be used to improve CADASIL mouse models. We hypothesize that a set of vascular proteins accumulate in CADASIL patients that are not expressed in mouse blood vessels. If true, then transgenic expression of these proteins has the potential to improve mouse models. Our experimental strategy includes: 1) screening the Human Protein Atlas for new brain vascular markers; 2) identifying human specific markers by comparative immunohistochemistry; 3) identification of new human specific markers that colocalize with conformationally altered NOTCH3 in human tissue; 4) experimental analysis of human-specific CADASIL proteins in cell culture for functions relevant to CADASIL. In preliminary work aimed to prove feasibility, we downloaded and analyzed over 150,000 images from the Human Protein Atlas in search of novel vascular markers. We then used immunohistochemistry to define two new human specific vascular proteins that co-localize with mutant NOTCH3 protein in CADASIL. Ultimately, this project will identify new proteins important in the genesis of CADASIL; it is likely that absence of these proteins in mice may explain the limited phenotypes of current preclinical SVD models.

摘要