权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Notch1 and APP signaling in cerebral microvascular dysfunction

Notch1和APP信号传导在脑微血管功能障碍中的作用

基本信息

批准号：
10196086
负责人：
Young-wook Jun
金额：
$ 43.87万
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：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10196086
关键词：
3-Dimensional Abeta clearance Adherens Junction Adhesives Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Arteries Automobile Driving Biological Biomimetics Biosensor Blood Blood - brain barrier anatomy Blood Vessels Brain Cadherins Cell membrane Cell surface Cell-Cell Adhesion Cerebral small vessel disease Cerebrovascular Circulation Cerebrum Classification Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Dementia Dependence Development Diffuse Disease Elderly Endothelial Cells Endothelium Engineering Equilibrium Exposure to Feedback Genetic Transcription Health Homeostasis Human Human Engineering Impaired cognition Impairment In Situ Intercellular Junctions Laboratories Link Lymphatic Lymphatic clearance Mechanics Mediating Mediator of activation protein Membrane Microdomains Microfluidics Microscopy Microvascular Dysfunction Modeling Molecular Monitor Onset of illness Pathogenesis Pathologic Pathology Pathway interactions Patients Peptides Permeability Preventive therapy Process Production Protein Dynamics Proteolysis Proteolytic Processing Recombinants Research Signal Transduction Signaling Protein Technology Therapeutic Intervention Time Tissues Transmembrane Domain Vascular Endothelial Cell abeta accumulation abeta deposition age related amyloid pathology amyloid precursor protein processing base brain endothelial cell cadherin 5 cerebral microvasculature disability early detection biomarkers functional loss gamma secretase innovation insight interdisciplinary approach interstitial lymphatic drainage lymphatic dysfunction lymphatic vasculature lymphatic vessel mouse model mutant neuroimaging novel older patient organ on a chip preventive intervention receptor recruit single molecule spatiotemporal

项目摘要

Project Summary/Abstract Cognitive dysfunction and dementia are a major health challenge for the elderly and one of the primary underlying causes, cerebral small vessel disease (CSVD), contributes to 50% of all dementias worldwide. The breakdown of blood vascular barrier and impaired lymphatic clearance associated with CSVD are considered early biomarkers of human cognitive dysfunction, and reduced cortical cerebral blood flow and microvascular leak are observed during disease onset in both dementia patients and mouse models. One classification of CSVD, amyloidal CSVD, is characterized by the increased deposition of amyloid beta (Aβ), derived from the pathologic proteolytic processing of amyloid precursor protein (APP), along and within the brain microvasculature. Amyloidal CSVD appears in nearly all elderly patients with dementia and in roughly 65-85% of the elderly without dementia. Reciprocally, impaired blood and lymphatic microvasculature undermine Aβ clearance from the brain microenvironment, exacerbating Aβ deposition and CSVD pathology. Blood and lymphatic microvascular dysfunction during amyloidal CSVD are characterized by the disintegration of vascular endothelial cell-cell adhesions and their primary mediator, vascular endothelial cadherin (VE-cadherin). However, molecular mechanisms that link Aβ to changes in blood and lymphatic vessel permeability via endothelial cell junctional instability and VE-cadherin disassembly are unknown. Recently we have identified a novel mechanism by which the proteolytic processing of the Notch1 receptor is critical for the promotion of microvascular barrier function through the enhancement of endothelial VE-cadherin junctions. Additionally, our preliminary data suggest that both Notch1 and APP required association with VE-cadherin junctions for their proper processing by γ-secretase. Here, building upon mechanistic insights uncovered by two highly complementary laboratories (Kutys and Jun labs), our research team will apply engineering and experimental approaches that span biological scales from single molecules to 3D human biomimetic microvessels to investigate our central hypothesis that increased cerebral Aβ disrupts a critical signaling balance of Notch1 and/or APP processing at VE-cadherin junctions to drive blood and lymphatic microvascular dysfunction. Together, these studies will define new homeostatic mechanisms regulating brain blood and lymphatic microvascular function, how these molecular processes may be disrupted by Aβ, and potentially identify new targets for preventative and therapeutic intervention.

项目总结/摘要认知功能障碍和痴呆症是老年人面临的主要健康挑战，也是主要的潜在问题之一脑小血管病（CSVD）是全球50%的痴呆症的病因。击穿与CSVD相关的血管屏障和淋巴清除受损被认为是早期人类认知功能障碍、皮质脑血流量减少和微血管渗漏的生物标志物是在痴呆患者和小鼠模型中的疾病发作期间观察到。CSVD的一种分类，淀粉样CSVD的特征是淀粉样β（Aβ）沉积增加，来源于病理性淀粉样前体蛋白（APP）的蛋白水解加工，沿着和在脑微血管系统内。淀粉样的 CSVD几乎出现在所有老年痴呆症患者中，大约65-85%的老年人没有痴呆症。反过来，受损的血液和淋巴微血管系统破坏了Aβ从大脑中的清除微环境，加剧Aβ沉积和CSVD病理。血液和淋巴微血管淀粉样CSVD期间的功能障碍的特征在于血管内皮细胞-细胞粘附及其主要介质，血管内皮钙粘蛋白（VE-钙粘蛋白）。然而，分子通过内皮细胞连接蛋白将Aβ与血液和淋巴管通透性变化联系起来的机制不稳定性和VE-钙粘蛋白分解是未知的。最近我们发现了一种新的机制， Notch 1受体的蛋白水解加工对于促进微血管屏障功能是至关重要的通过增强内皮VE-钙粘蛋白连接。此外，我们的初步数据表明， Notch 1和APP都需要与VE-钙粘蛋白连接结合，以通过γ-分泌酶进行适当加工。在这里，建立在两个高度互补的实验室（Kutys和Jun 实验室），我们的研究团队将应用工程和实验方法，跨越生物尺度，单分子到3D人类仿生微血管来研究我们的中心假设，脑Aβ破坏了VE-钙粘蛋白连接处Notch 1和/或APP加工的关键信号平衡，导致血液和淋巴微血管功能障碍。总之，这些研究将定义新的稳态调节脑血液和淋巴微血管功能的机制，这些分子过程如何被Aβ破坏，并有可能找到预防和治疗干预的新靶点。