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.

抽象的在美国，每 19 名死亡者中就有 1 人死于中风，以及心血管疾病造成的损失 2009 年中风带来的损失为 3,120 亿美元（相比之下，所有癌症的损失为 2,280 亿美元）。脑小血管疾病 (SVD) 占中风的比例高达 30%，是导致与年龄相关的认知能力下降和残疾。编码 IV 型胶原蛋白 alpha 1 (COL4A1) 的基因的罕见突变导致遗传性 SVD 包括脑白质疏松、皮质下微出血、孔脑畸形、颅内动脉瘤、血管周围扩大间隙、腔隙性梗死和出血性中风。常见的 COL4A1 变体已关联颅内动脉瘤、动脉钙化、深部脑出血、腔隙性缺血性中风、减少白质体积和白质脑病。 COL4A1 突变如何导致 SVD 尚不清楚，代表了我们当前知识的巨大差距。该提案代表了一个综合性和整体性的了解 SVD 发病机制的方法。我们多元化团队的目标是确定新的 SVD 病因以及可以针对预防、延迟或减少 SVD 损害的致病机制。我们的具体重点是 COL4A1 突变的细胞内和细胞外后果，然而，我们也有识别新的 SVD 子类并开辟不相关的研究领域的潜力。

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）

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

I 型和 V 型原胶原三螺旋使用不同的分子集合子集来进行 rER 中的赖氨酸翻译后修饰。

DOI：
发表时间：
2021-01
期刊：
影响因子：
0
作者：
Ishikawa, Yoshihiro;Taga, Yuki;Zientek, Keith;Mizuno, Nobuyo;Salo, Antti M;Semenova, Olesya;Tufa, Sara F;Keene, Douglas R;Holden, Paul;Mizuno, Kazunori;Gould, Douglas B;Myllyharju, Johanna;Bächinger, Hans Peter
通讯作者：
Bächinger, Hans Peter

Rare metabolic disease mimicking COL4A1/COL4A2 fetal brain phenotype.

模仿 COL4A1/COL4A2 胎儿脑表型的罕见代谢疾病。

DOI：
发表时间：
2022-12
期刊：
影响因子：
0
作者：
Coste, T;Aloui, C;Petit, F;Moutton, S;Devisme, L;Wells, C F;Leboucq, N;Verpillat, P;Yvert, M;Rivier, F;Tournier
通讯作者：
Tournier

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

突变体 HSP47 的异常结合会影响 I 型胶原的翻译后修饰并导致成骨不全。

DOI：
发表时间：
2021
期刊：
影响因子：
4.5
作者：
Syx, Delfien;Ishikawa, Yoshihiro;Gebauer, Jan;Boudko, Sergei P;Guillemyn, Brecht;Van Damme, Tim;D'hondt, Sanne;Symoens, Sofie;Nampoothiri, Sheela;Gould, Douglas B;Baumann, Ulrich;Bächinger, Hans Peter;Malfait, Fransiska
通讯作者：
Malfait, Fransiska

The novel missense mutation Met48Lys in FKBP22 changes its structure and functions.

FKBP22 中新的错义突变 Met48Lys 改变了其结构和功能。

DOI：
发表时间：
2020
期刊：
影响因子：
4.6
作者：
Ishikawa, Yoshihiro;Mizuno, Nobuyo;Holden, Paul;Lim, Pei Jin;Gould, Douglas B;Rohrbach, Marianne;Giunta, Cecilia;Bächinger, Hans Peter
通讯作者：
Bächinger, Hans Peter

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

胎儿中的 COL4A1/COL4A2 和遗传性血小板疾病基因变异显示颅内出血。

DOI：
发表时间：
2022-05
期刊：
影响因子：
3
作者：
Coste, Thibault;Vincent;Stichelbout, Morgane;Devisme, Louise;Gelot, Antoinette;Deryabin, Igor;Pelluard, Fanny;Aloui, Chaker;Leutenegger, Anne;Jouannic, Jean;Héron, Delphine;Gould, Douglas B;Tournier
通讯作者：
Tournier