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.

项目总结