Investigating Angiogenic Mediators as Biomarkers and Targets for Rescuing Small Vessel Disease in a Model of VCID

研究血管生成介质作为 VCID 模型中挽救小血管疾病的生物标志物和靶标

• 批准号: 10230371
• 负责人: Zachary Winder
• 金额: $ 3.48万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230371
• 关键词: Aging; Alzheimer' s Disease; Analysis of Covariance; Animal Model; Autopsy; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Brain; Cells; Cerebrovascular Disorders; Clinical; Cognitive; Communication; Data; Dementia; Development; Diagnosis; Diet; Disease; Disease Progression; Environment; Evaluation; Extracellular Matrix; Extracellular Matrix Degradation; Future; Genotype; Hematoxylin and Eosin Staining Method; Histology; Human; Hyperhomocysteinemia; Hypoxia; Immunoassay; Immunohistochemistry; Impaired cognition; Infarction; Linear Models; Link; Liquid substance; Magnetic Resonance Imaging; Measures; Mediation; Mediator of activation protein; Mentorship; Microvascular Dysfunction; Modeling; Monitor; Mus; Neurocognitive; Neurosciences; Oral; Outcome; PGF gene; Pathologic; Pathology; Patients; Physicians; Plasma; Play; Pre-Clinical Model; Prevalence; Recording of previous events; Resolution; Role; Scanning; Scientist; Sensitivity and Specificity; Statistical Models; Technology; Testing; Tissue Sample; Tissues; Training; Transgenic Mice; Up-Regulation; White Matter Hyperintensity; Work; angiogenesis; base; biomarker discovery; brain tissue; burden of illness; candidate marker; career; cerebrovascular pathology; cohort; cost; cost effective; digital; histological stains; human tissue; imaging modality; in vivo; magnetic resonance imaging biomarker; mouse model; nano-string; neuroimaging; neuropathology; novel therapeutics; prevent; protein expression; response; targeted treatment; therapeutic target; tool; vascular cognitive impairment and dementia

Project Summary Dementia is a disorder characterized by a significant decline from baseline in one or more cognitive domains that interferes with independence. Prevalence of dementia worldwide is estimated at 50 million with that number expected to triple by 2030, coming with a cost of roughly $2 trillion. Vascular Contributions to Cognitive Impairment and Dementia (VCID) is the second leading cause of dementia and is the umbrella term used to characterize patients with cognitive dysfunction as a result of cerebrovascular pathology. Small vessel disease (SVD) is one type of cerebrovascular pathology that is found in roughly 50% of patients with VCID. Common neuropathological findings associated with SVD include microinfarctions, microhemorrhages, and arteriolosclerosis. While MRI identifies larger infarctions and microbleeds, it is limited by resolution of the scan. Therefore, identification of these pathologies has proven difficult outside of post-mortem evaluation. White matter hyperintensities (WMH) on MRI have become the standard used to evaluate SVD; but are limited by their cost and lack of targetable mechanisms for preventing progression of the disease. In this proposal, we explore the role of angiogenic mediators as modifiable fluid biomarkers, which can be used to evaluate SVD and potentially altered to decrease progression of SVD. We focus on placental growth factor (PLGF) due to its upregulation in hypoxic environments, which is found in arteriolosclerosis. Our preliminary data suggests that patients with VCID have increased PLGF concentrations compared to controls. Additionally, previous studies have shown that PLGF induces degradation of the extracellular matrix and the blood brain barrier, which are initiating steps in formation of microhemorrhages. This proposal first seeks to evaluate whether plasma PLGF is upregulated in patients with increased levels of SVD pathology, as measured in post-mortem neuropathological evaluation (Aim 1a) and whether PLGF has a tight spatial co-localization with SVD pathology in human tissue (Aim 1b). This will demonstrate the viability of PLGF as a fluid biomarker for SVD pathology. Secondly, we will use a diet to induce a well-established model of VCID in PLGF-KO transgenic mice, to evaluate the role of PLGF on development of microhemorrhages (Aim 2). This aim will help support our hypothesis that reducing availability of PLGF will reduce the burden of microhemorrhages in patients with SVD. This mechanism can then be used to develop novel therapeutics in order to halt the progression of VCID. Through this proposal and under the mentorship of Dr. Wilcock and Dr. Jicha at the Sanders-Brown Center on Aging, the applicant will investigate the utility of PLGF as a modifiable fluid biomarker for SVD. In doing so, the applicant will be trained in immunoassay-based biomarker discovery, statistical linear modeling, clinical patient evaluation, immunohistochemistry, pathological histology evaluation, and oral and written scientific communications for a future career as an independent physician-scientist.

项目摘要 痴呆症是一种疾病，其特征是一个或多个认知的基线显着下降 干扰独立性的领域。全球痴呆症患病率估计为5000万 这个数字预计到2030年将达到三倍，成本约为2万亿美元。血管贡献 认知障碍和痴呆症（VCID）是痴呆症的第二主要原因，是伞术 用于表征由于脑血管病理而导致认知功能障碍的患者。小船 疾病（SVD）是一种脑血管病理，在大约50％的VCID患者中发现。 与SVD相关的常见神经病理学发现包括微含量，微视感和 动脉粥样硬化。 MRI鉴定出较大的梗塞和微粒，但受扫描的分辨率限制。 因此，事实证明，在验尸评估之外，很难识别这些病理。白质 MRI上的高强度（WMH）已成为评估SVD的标准。但受其费用的限制 并且缺乏预防疾病进展的目标机制。在此提案中，我们探索 血管生成介质作为可修改的流体生物标志物的作用，可用于评估SVD并潜在地评估 改变以减少SVD的进展。由于胎盘生长因子（PLGF）的上调 低氧环境，在小动脉粥样硬化中发现。我们的初步数据表明VCID患者 与对照组相比，PLGF浓度增加。此外，以前的研究表明PLGF 诱导细胞外基质和血脑屏障的降解，它们正在构成步骤 微视点。该提案首先试图评估血浆PLGF是否在患者中上调 如验尸后神经病理学评估（AIM 1A）和 PLGF是否与人体组织中的SVD病理具有紧密的空间共定位（AIM 1B）。这会 证明PLGF作为SVD病理的流体生物标志物的生存能力。其次，我们将使用饮食诱导 PLGF-KO转基因小鼠中VCID的建立良好模型，以评估PLGF在开发中的作用 微视角（AIM 2）。这个目标将有助于支持我们的假设，即减少PLGF的可用性将 减轻SVD患者的微生物诊所的负担。然后可以使用这种机制来发展 新型治疗学是为了停止VCID的进展。通过这个建议以及在 Wilcock博士和Jicha博士在Sanders-Brown衰老中心，申请人将调查PLGF的实用程序 作为SVD的可修改流体生物标志物。这样，申请人将接受以免疫测定的培训 生物标志物发现，统计线性建模，临床患者评估，免疫组织化学，病理学 组织学评估，以及作为独立职业的未来职业的口头和书面科学沟通 医师科学家。