High Content Sceening for Hereditary Stroke Syndrome

遗传性中风综合症的高内涵筛查

基本信息

批准号：
8731282
负责人：
DEAN Yaw LI
金额：
$ 32.27万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8731282
关键词：
Animal Model Animals Biological Assay Blood Vessels CCM1 gene Cavernous Malformation Cell Culture System Cell Line Cells Cerebrum Chemicals Chronic Classification Clinical Trials Data Defect Dermal Development Disease Endothelial Cells Endothelium Genes Genetic Human Image Imaging Techniques In Vitro Inherited Knockout Mice Lesion Libraries Longitudinal Studies Machine Learning Magnetic Resonance Imaging Measures Medical Medicine Modeling Molecular Target Mus Mutation Neuraxis Pathogenesis Pathway interactions Patients Pattern Permeability Phenotype Pilot Projects Reporting Rheumatoid Arthritis Sepsis Small Interfering RNA Stroke Syndrome Techniques Telangiectasis Testing Therapeutic Toxic effect Universities Utah Vascular Diseases Work base electric impedance flexibility high throughput analysis in vitro Assay in vivo monolayer mouse model nervous system disorder neurosurgery novel pharmacophore preclinical study public health relevance screening small molecule small molecule libraries tempol

项目摘要

DESCRIPTION (provided by applicant): Cerebral Cavernous Malformation (CCM) is a hereditary stroke syndrome that has no treatment other than neurosurgery. Loss of one of three genes causes CCM. By reducing the expression of one of these genes (CCM2) in the cells that line blood vessels (endothelial cells), unique structural and functional phenotypes result. We will use a chemical suppression screen in cell culture systems to discover small molecules that rescue these distinct phenotypes. Our high-throughput platform consists of two primary screens: the first is an imaging screen with machine-learning based phenotype analysis; the second screen uses electric cell substrate impedance sensing to detect changes in endothelial barrier function. We will then further screen the top candidate compounds in a mouse model of human CCM disease. The result of this project will be personalized medicine candidates for the treatment of CCM caused by mutations in the CCM2 gene.

描述（由申请人提供）：脑海绵状畸形（CCM）是一种遗传性中风综合征，除了神经外科手术外没有治疗。三个基因之一的损失导致CCM。通过降低这些基因（CCM2）的表达（CCM2）在排列血管（内皮细胞）的细胞中，从而产生了独特的结构和功能表型。我们将在细胞培养系统中使用化学抑制筛选，发现拯救这些不同表型的小分子。我们的高通量平台由两个主要屏幕组成：第一个是一个具有基于机器学习的表型分析的成像屏幕；第二个屏幕使用电细胞底物阻抗感测来检测内皮屏障功能的变化。然后，我们将在人类CCM疾病的小鼠模型中进一步筛选顶级候选化合物。该项目的结果将是个性化的候选药物，用于治疗由CCM2基因突变引起的CCM。