Genetic and Mechanistic Study of Cerebral Small Vessel Disease

脑小血管病的遗传学及机制研究

基本信息

批准号：
10213843
负责人：
Douglas Gould
金额：
$ 61.06万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213843
关键词：
Age-associated memory impairment Anabolism Area Basement membrane Biological Process Brain hemorrhage Cardiovascular Diseases Cell Surface Receptors Cells Cerebral hemisphere hemorrhage Cerebral small vessel disease Cerebrovascular Disorders Cerebrum Cessation of life Childhood Collagen Collagen Gene Collagen Type IV Defect Development Disease Distal Enzymes Etiology Failure Genes Genetic Genomic approach Goals Golgi Apparatus Growth Factor Human Genetics Immunoprecipitation Inherited Intervention Intracranial Aneurysm Ischemic Stroke Isotope Labeling Knowledge Lacunar Infarctions Lead Leukoaraiosis Leukoencephalopathy Life Malignant Neoplasms Microvascular Dysfunction Molecular Molecular Genetics Mutant Strains Mice Mutation Outcome Pathogenesis Pathogenicity Pathway interactions Patients Pericytes Perinatal Pharmacology Phenotype Prevention Process Proteins Proteomics Research Severities Signal Pathway Signal Transduction Signal Transduction Pathway Small Interfering RNA Stroke Techniques Testing Therapeutic United States Variant Vascular Endothelial Cell age related angiogenesis base calcification cognitive disability combinatorial cost disability disease-causing mutation exome extracellular fetal genetic approach genetic resource genome-wide holistic approach improved innovation knock-down lead candidate mutant new therapeutic target novel precision medicine prevent therapeutic target time use white matter

项目摘要

Abstract Strokes account for one out of every 19 deaths in the United States and the cost for cardiovascular disease and strokes in 2009 was $312 billion dollars (compared to $228 billion for all cancers). Cerebral small vessel diseases (SVD) account for up to 30% of strokes and are a leading cause of age-related cognitive decline and disability. Rare mutations in the genes encoding collagen type IV alpha 1 (COL4A1) cause inherited SVD including leukoaraiosis, subcortical microbleeds, porencephaly, intracranial aneurysms, enlarged perivascular spaces, lacunar infarctions and hemorrhagic strokes. Common COL4A1 variants have been associated intracranial aneurysms, arterial calcification, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and leukoencephalopathy. How COL4A1 mutations cause SVD is unknown and represents a significant gap in our current knowledge. This proposal represents an integrated and holistic approach to understand SVD pathogenesis. The goal of our diverse team is to identify novel SVD etiologies and pathogenic mechanisms that can be targeted to prevent, delay or reduce damage from SVD. Our specific focus is on the intracellular and extracellular consequences of COL4A1 mutations, yet, we also have the potential to identity novel SVD subclasses and break open unrelated areas of research.

抽象的中风占美国每19例死亡中的一个，而心血管疾病的费用 2009年的中风为3120亿美元（相比之下，所有癌症的价格为2280亿美元）。脑小容器疾病（SVD）占中风的30％，是与年龄有关的认知能力下降和残疾。编码IV型α1（COL4A1）的基因中的罕见突变导致遗传SVD 包括白血病，皮质下微粒，毛脑，颅内动脉瘤，血管周围肿大空间，空隙梗塞和出血性中风。常见的col4a1变体已经关联颅内动脉瘤，动脉钙化，深度脑内出血，lacunar缺血性中风，减少白质体积和白血病。 COL4A1突变如何引起SVD未知，并且在我们当前的知识上代表了一个重大差距。该提案代表了一个综合而整体的了解SVD发病机理的方法。我们多元化团队的目标是确定新颖的SVD病因以及可以针对性的致病机制，以防止，延迟或减少SVD损害。我们的具体重点是Col4a1突变的细胞内和细胞外后果，但是，我们也有身份的潜力新型SVD子类并破坏开放无关的研究领域。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rare metabolic disease mimicking COL4A1/COL4A2 fetal brain phenotype.

DOI：
10.1002/uog.26046
发表时间：
2022-12
期刊：
ULTRASOUND IN OBSTETRICS & GYNECOLOGY
影响因子：
7.1
作者：
Coste, T.;Aloui, C.;Petit, F.;Moutton, S.;Devisme, L.;Wells, C. F.;Leboucq, N.;Verpillat, P.;Yvert, M.;Rivier, F.;Tournier-Lasserve, E.
通讯作者：
Tournier-Lasserve, E.

Aberrant binding of mutant HSP47 affects posttranslational modification of type I collagen and leads to osteogenesis imperfecta.

DOI：
10.1371/journal.pgen.1009339
发表时间：
2021-03
期刊：
PLoS genetics
影响因子：
4.5
作者：
Syx D;Ishikawa Y;Gebauer J;Boudko SP;Guillemyn B;Van Damme T;D'hondt S;Symoens S;Nampoothiri S;Gould DB;Baumann U;Bächinger HP;Malfait F
通讯作者：
Malfait F

Type I and type V procollagen triple helix uses different subsets of the molecular ensemble for lysine posttranslational modifications in the rER.

DOI：
10.1016/j.jbc.2021.100453
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Ishikawa Y;Taga Y;Zientek K;Mizuno N;Salo AM;Semenova O;Tufa SF;Keene DR;Holden P;Mizuno K;Gould DB;Myllyharju J;Bächinger HP
通讯作者：
Bächinger HP

COL4A1/COL4A2 and inherited platelet disorder gene variants in fetuses showing intracranial hemorrhage.