Revealing novel pathogenic and repairing mechanisms of CADASIL disease.

揭示 CADASIL 疾病的新致病和修复机制。

• 批准号: 10419211
• 负责人: LI-RU ZHAO
• 金额: $ 49.52万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10419211
• 关键词: Adult; Affect; Antibodies; Area; Arterial Disorder; Arteries; Automobile Driving; Biological; Biological Assay; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Bone Marrow; Brain; Cancer Patient; Cells; Cerebral small vessel disease; Cerebrovascular Disorders; Cerebrum; Cessation of life; Combined Modality Therapy; Data; Defect; Dementia; Deposition; Disease; Disease Progression; Extracellular Domain; Extravasation; FDA approved; Functional disorder; Future; Gene Mutation; Genes; Genetic; Granulocyte Colony-Stimulating Factor; Growth Factor; Hematopoietic Cell Growth Factors; Image; Immunoglobulin G; Impaired cognition; Impairment; Induced Mutation; Inherited; Intervention; Ischemic Stroke; Knowledge; Methods; Microvascular Dysfunction; Missense Mutation; Molecular; Mus; Mutation; NOTCH3 gene; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pericytes; Pharmacology; Play; Recovery; Recurrence; Research; Research Priority; Role; Route; Signal Transduction; Smooth Muscle Myocytes; Stem Cell Factor; Stroke; Subcortical Infarctions; Subcortical Leukoencephalopathy; Testing; Therapeutic; Thrombosis; Toxic effect; Transgenic Mice; Treatment Factor; United States National Institutes of Health; Up-Regulation; VEGFA gene; Vascular Dementia; Vascular Endothelial Growth Factors; Vascular Smooth Muscle; base; bevacizumab; cellular pathology; cerebral capillary; cerebrovascular; cerebrovascular pathology; chemotherapy; density; disability; enhancing factor; improved; innovation; insight; middle age; mortality; mouse model; neuron loss; novel; preclinical study; receptor; recombinase-mediated cassette exchange; repaired; stem cells; therapeutic development; transcriptome sequencing; two photon microscopy; two-photon; vascular cognitive impairment and dementia

PROJECT SUMMARY/ABSTRACT Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) represents the most common form of hereditary ischemic stroke (microinfarcts) and vascular dementia. CADASIL is a monogenic cerebral small vessel disease driven by progressive degeneration of mural cells due to NOTCH3 gene mutation in the mural cells (vascular smooth muscle cells and pericytes). This vascular degeneration-induced dementia is one of the diseases sharing a similar pathological mechanism of “Vascular Contributions to Cognitive Impairment and Dementia” (VCID). The NIH has designated VCID as a critical research area requiring studies to explore new molecular mechanisms of cerebrovascular pathology and potential treatments for vascular dementia. CADASIL mainly affects young and middle-aged adults and causes severe disability and early death. No treatment is available to stop or delay disease progression for CADASIL. Although the causative role of NOTCH3 gene mutation in CADASIL was revealed in 1996, it still remains unclear today how NOTCH3 mutation drives cerebrovascular defects. The lack of this pathogenic knowledge creates a critical barrier for the development of therapeutic strategies for CADASIL. Our earlier studies have demonstrated that combined treatment of two hematopoietic growth factors, stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) ameliorates vascular smooth muscle cell degeneration, cerebrovascular regression, capillary thrombosis, microinfarcts, blood-brain barrier (BBB) leakage, and cognitive impairments in a mouse model of CADASIL (TgNotch3R90C mice). It remains to be determined, however, how the SCF+G-CSF treatment enhances cerebrovascular repair in TgNotch3R90C mice. The objective of this application is to determine a novel pathogenic mechanism for CADASIL and the underlying mechanism for SCF+G-CSF-enhanced cerebrovascular repair in TgNotch3R90C mice. Using 2- photon cortical capillary circulation imaging, BBB integrity assay, pharmacological intervention, and Cre-Lox technology, this application will define how impaired cerebral capillary circulation in TgNotch3R90C mice is improved by SCF+G-CSF treatment (Aim 1), how cerebral capillary leakage in TgNotch3R90C mice is ameliorated by SCF+G-CSF treatment (Aim 2), and how mural cell-produced pathogenic molecules drive progressive cerebrovascular defects and how SCF+G-CSF treatment ameliorates the cerebrovascular defects by modulating the pathogenic molecules (Aim 3) in TgNotch3R90C mice. It is expected that the findings of this mechanistic study will significantly advance the understanding of the pathogenesis for CADASIL and will reveal new targets and new routes to develop novel treatments for CADASIL. This proposed study fits within the research priorities of NIH-highlighted VCID research.

项目摘要/摘要 常染色体显性遗传性脑动脉病合并皮质下梗塞和白质脑病(CADASIL) 代表最常见的遗传性缺血性中风(微梗塞)和血管性痴呆。 CADASIL是一种单基因脑血管疾病，由壁细胞进行性退行性变引起 对壁细胞(血管平滑肌细胞和周细胞)中NOTCH3基因突变的影响。这根血管 退行性痴呆是一种与血管疾病有着相似的病理机制的疾病 认知障碍和痴呆症的贡献“(VCID)。美国国家卫生研究院已将VCID指定为危急 研究领域需要探索脑血管病理和脑血管疾病的新分子机制 血管性痴呆症的潜在治疗方法。 CADASIL主要影响青壮年，导致严重残疾和过早死亡。不是 CADASIL的治疗可以阻止或延缓疾病的进展。尽管起因的作用是 NOTCH3基因突变在1996年被发现，至今仍不清楚NOTCH3是如何 突变会导致脑血管缺陷。这种致病知识的缺乏为 CADASIL治疗策略的发展。 我们早期的研究表明，联合治疗两种造血生长因子，干细胞 细胞因子(SCF)和粒细胞集落刺激因子(G-CSF)改善血管 平滑肌细胞变性、脑血管退行性变、毛细血管血栓形成、微梗塞、血脑 屏障(BBB)渗漏与CADASIL小鼠模型(TgNotch3R90C小鼠)的认知障碍。它 然而，SCF+G-CSF治疗如何促进脑血管修复仍有待确定 TgNotch3R90C小鼠。 本应用的目的是确定CADASIL的一种新的致病机制和 SCF+G-CSF促进TgNotch3R90C小鼠脑血管修复的机制使用2- 光子皮质毛细血管循环成像、血脑屏障完整性分析、药物干预和Cre-Lox 技术，这项应用将定义TgNotch3R90C小鼠大脑毛细血管循环受损的程度 干细胞因子+粒细胞集落刺激因子治疗改善TgNotch3R90C小鼠脑毛细血管渗漏 通过SCF+G-CSF治疗(目标2)得到改善，以及壁细胞如何产生致病分子驱动 进展性脑血管畸形与SCF+G-CSF治疗改善脑血管畸形 通过调节TgNotch3R90C小鼠的致病分子(Aim 3)。 预计这一机制研究的结果将大大促进对 CADASIL的发病机制将揭示新的靶点和新的途径来开发新的治疗方法 CADASIL。这项拟议的研究符合美国国立卫生研究院强调的VCID研究的优先研究重点。