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 痴呆是一种以一种或多种认知功能从基线显著下降为特征的疾病， 这些领域干扰了独立性。全球痴呆症患病率估计为5000万， 到2030年，这一数字预计将增加两倍，成本约为2万亿美元。血管对 认知障碍和痴呆症（VCID）是痴呆症的第二大原因，是一个总括术语。 用于表征脑血管病理导致的认知功能障碍患者。小血管 脑血管病（SVD）是一种脑血管病变，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梗死、微血管扩张和微血管扩张。 小动脉硬化虽然MRI可以识别较大的梗死和微出血，但它受到扫描分辨率的限制。 因此，这些病理的鉴定已被证明很难在死后评价之外进行。白色物质 MRI上的高信号（WMH）已成为用于评估SVD的标准;但受到成本的限制 以及缺乏预防疾病进展的靶向机制。在本建议中，我们探讨 血管生成介质作为可改变的液体生物标志物的作用，可用于评价SVD， 改变以减少SVD的进展。我们专注于胎盘生长因子（PLGF），因为它的上调， 缺氧环境，这是发现在小动脉硬化。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，这是形成的起始步骤 微型摄像机该建议首先试图评估血浆PLGF是否在患有糖尿病的患者中上调。 SVD病理学水平升高，如尸检神经病理学评价（目的1a）所示，以及 PLGF是否与人体组织中的SVD病理学具有紧密的空间共定位（目的1b）。这将 证明PLGF作为SVD病理学的流体生物标志物的可行性。其次，我们将使用饮食诱导 在PLGF-KO转基因小鼠中建立良好的VCID模型，以评估PLGF对VCID发展的作用。 显微镜下观察（Aim 2）。这一目标将有助于支持我们的假设，即减少PLGF的可用性将 减少SVD患者的微血管扩张负担。这种机制可以用来开发 新的治疗方法，以阻止VCID的进展。通过这一提议，并在 博士Wilcock和Sanders-Brown老龄化中心的Jicha博士，申请人将调查PLGF的效用 作为SVD的可变液体生物标志物。在此过程中，申请人将接受基于免疫测定的 生物标志物发现，统计线性建模，临床患者评价，免疫组织化学，病理学 组织学评估，以及口头和书面的科学交流，为未来的职业生涯作为一个独立的 物理学家兼科学家