Molecular Interactions in Cerebral Small Vessel Disease

脑小血管疾病的分子相互作用

基本信息

批准号：
9275315
负责人：
Michael M Wang
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2017-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275315
关键词：
Affect Alzheimer&apos s Disease Arteries Automobile Driving Basement membrane Binding Biochemical Blood Vessels Brain Diseases CADASIL Cell Death Cell Separation Cerebral small vessel disease Cessation of life Collagen Type IV Complex Data Dementia Disease Elderly Epigenetic Process Extracellular Matrix Feedback Genes Genetic Genetic Transcription Human Impairment Knowledge Maps Membrane Proteins Microvascular Dysfunction Modeling Molecular Mus Mutate Mutation NOTCH3 gene Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Play Population Process Protein Region Proteins Regulation Role Severity of illness Smooth Muscle Smooth Muscle Myocytes Stroke Testing Tissues Up-Regulation Vascular Dementia Vascular Smooth Muscle Veterans design mouse model mutant notch protein prototype public health relevance selective expression targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most widely recognized monogenic form of small vessel disease (SVD), a common cause of stroke and dementia. By comprehensively understanding the molecular basis of CADASIL, we hope to identify molecular pathways which can be targeted to treat SVD. Most patients with CADASIL have mutations in NOTCH3, a gene expressed selectively in vascular smooth muscle. This has led to the hypothesis that CADASIL is caused by NOTCH3-induced impairment of protein clearance, cell separation, and smooth muscle cell death. Recently, mutations in the major basement membrane protein COL4A1 (vascular type IV collagen) have also been identified in familial SVD, suggesting that smooth muscle extracellular matrix abnormalities can also result in SVD. In this proposal, we hypothesize that NOTCH3 and COL4A form a functional unit that plays a central role in SVD. In preliminary studies, we show that 1) NOTCH3 and COL4A1 both accumulate and co-localize in blood vessels in CADASIL; 2) NOTCH3 and COL4A1 form stable molecular complexes; 3) NOTCH3 function is blocked by COL4A1; 4) mutant NOTCH3 protein upregulates COL4A1 transcription. Consequently, we hypothesize that mutant NOTCH3 enhances COL4A1 accumulation, which blocks Notch regulation of smooth muscle genes and inhibits Notch clearance, leading to smooth muscle death. Three aims will be pursued: (1) We will biochemically characterize interactions between NOTCH3 and COL4A. (2) We will test whether COL4A inhibits NOTCH function and clearance and promotes smooth muscle cell death. (3) We will examine NOTCH3 and COL4A in CADASIL mice and human cases of CADASIL to determine whether CADASIL is associated with genetic or epigenetic changes in the COL4A locus. By understanding the molecular underpinnings of CADASIL in detail, we hope to accrue knowledge essential for developing rational treatments for SVD.

描述（由申请人提供）：伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病 (CADASIL) 是最广泛认可的单基因型小血管病 (SVD)，是中风和痴呆的常见原因。通过全面了解 CADASIL 的分子基础，我们希望找到可靶向治疗 SVD 的分子途径。大多数 CADASIL 患者都有 NOTCH3 突变，NOTCH3 是一种在血管平滑肌中选择性表达的基因。这导致了这样的假设：CADASIL 是由 NOTCH3 诱导的蛋白质清除、细胞分离和平滑肌细胞死亡损伤引起的。最近，在家族性 SVD 中也发现了主要基底膜蛋白 COL4A1（血管 IV 型胶原蛋白）的突变，这表明平滑肌细胞外基质异常也可导致 SVD。在这个提议中，我们假设 NOTCH3 和 COL4A 形成一个在 SVD 中发挥核心作用的功能单元。在初步研究中，我们表明 1) NOTCH3 和 COL4A1 均在 CADASIL 的血管中积累并共定位； 2) NOTCH3和COL4A1形成稳定的分子复合物； 3）NOTCH3功能被COL4A1阻断； 4) 突变型NOTCH3蛋白上调COL4A1转录。因此，我们假设突变型NOTCH3会增强COL4A1的积累，从而阻断Notch对平滑肌基因的调节并抑制Notch清除，从而导致平滑肌死亡。我们将追求三个目标：（1）我们将从生化角度表征 NOTCH3 和 COL4A 之间的相互作用。 (2)我们将测试COL4A是否抑制NOTCH功能和清除并促进平滑肌细胞死亡。 (3) 我们将检查 CADASIL 小鼠和人类 CADASIL 病例中的 NOTCH3 和 COL4A，以确定 CADASIL 是否与 COL4A 基因座的遗传或表观遗传变化相关。通过详细了解 CADASIL 的分子基础，我们希望积累开发合理的 SVD 治疗方法所必需的知识。