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.

项目总结/摘要 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） 代表遗传性缺血性中风（微梗塞）和血管性痴呆的最常见形式。 CADASIL是一种单基因脑小血管疾病，由壁细胞进行性变性引起， 在壁细胞（血管平滑肌细胞和周细胞）中的NOTCH 3基因突变。这种血管 退行性痴呆是与血管性痴呆有相似病理机制的疾病之一， 对认知障碍和痴呆症的贡献”（VCID）。NIH已将VCID指定为关键 研究领域需要研究探索脑血管病理学的新分子机制， 血管性痴呆的潜在治疗方法 CADASIL主要影响青年和中年人，并导致严重残疾和早期死亡。没有 治疗可以阻止或延迟CADASIL的疾病进展。虽然因果作用 CADASIL中的NOTCH 3基因突变于1996年被发现，至今仍不清楚NOTCH 3如何在CADASIL中发挥作用。 突变导致脑血管缺陷缺乏这种病原学知识， 开发CADASIL的治疗策略。 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）（SCF+G-CSF）可改善血管内皮细胞增生， 平滑肌细胞变性，脑血管退化，毛细血管血栓形成，微梗塞，血脑 在CADASIL的小鼠模型（TgNotch 3R 90 C小鼠）中观察到了血脑屏障（BBB）渗漏和认知障碍。它 然而，SCF+G-CSF治疗如何增强脑血管修复仍有待确定。 TgNotch 3R 90 C小鼠。 本申请的目的是确定CADASIL的新致病机制， SCF+G-CSF增强TgNotch 3R 90 C小鼠脑血管修复的潜在机制。使用2- 光子皮层毛细血管循环成像、血脑屏障完整性测定、药物干预和Cre-Lox 技术，该应用将定义TgNotch 3R 90 C小鼠中受损的脑毛细血管循环是如何 通过SCF+G-CSF治疗（目的1）改善TgNotch 3R 90 C小鼠的脑毛细血管渗漏 通过SCF+G-CSF治疗改善（目的2），以及壁细胞产生的致病分子如何驱动 进行性脑血管缺陷以及SCF+G-CSF治疗如何改善脑血管缺陷 通过调节TgNotch 3R 90 C小鼠中的致病分子（Aim 3）。 预计这项机制研究的结果将大大促进对 CADASIL的发病机制，并将揭示新的目标和新的途径，以开发新的治疗方法， CADASIL。这项拟议的研究符合NIH强调的VCID研究的研究重点。