Genetic and Mechanistic Study of Cerebral Small Vessel Disease

脑小血管病的遗传学及机制研究

• 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
• 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

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.

摘要 在美国，每19例死亡中就有一例死于中风，心血管疾病的成本 2009年，中风为3120亿美元(相比之下，所有癌症的中风为2280亿美元)。脑部小血管 疾病(SVD)占中风的30%，是与年龄相关的认知能力下降和 残疾。编码IV型胶原α1(COL4A1)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、脑穿孔、颅内动脉瘤、血管周围扩大 腔隙、腔隙性脑梗塞和出血性中风。常见的COL4A1变种已经被关联 颅内动脉瘤，动脉钙化，脑深部出血，腔隙缺血性中风，减少 脑白质体积与白质脑病。COL4A1突变是如何导致SVD的尚不清楚 代表着我们目前知识中的一大差距。这项建议代表了一个综合性和整体性的 探讨SVD的发病机制。我们不同团队的目标是确定新的SVD病因 以及可以有针对性地预防、延迟或减少SVD造成的损害的致病机制。我们的特定 重点是COL4A1突变的细胞内和细胞外后果，然而，我们也有 有可能识别新的奇异值分解子类，并打开不相关的研究领域。

项目成果

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
• 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.

• DOI: 10.1002/pd.6113
• 发表时间: 2022-05
• 期刊: Prenatal diagnosis
• 影响因子: 3