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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要痴呆症是一种以一种或多种认知能力较基线显着下降为特征的疾病干扰独立性的领域。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。血管贡献认知障碍和痴呆症 (VCID) 是痴呆症的第二大原因，是一个总称用于表征因脑血管病理导致的认知功能障碍患者。小船 SVD 疾病 (SVD) 是一种脑血管病理类型，约 50% 的 VCID 患者有此症状。与 SVD 相关的常见神经病理学发现包括微梗塞、微出血和动脉硬化。虽然 MRI 可以识别较大的梗塞和微出血，但它受到扫描分辨率的限制。因此，事实证明，除了尸检评估之外，很难识别这些病理。白质 MRI 上的高信号（WMH）已成为评估 SVD 的标准；但受到成本的限制以及缺乏预防疾病进展的针对性机制。在本提案中，我们探讨了血管生成介质作为可修改的液体生物标志物的作用，可用于评估 SVD 和潜在的改变以减少 SVD 的进展。我们关注胎盘生长因子 (PLGF)，因为它在缺氧环境，见于动脉硬化。我们的初步数据表明 VCID 患者与对照相比，PLGF 浓度增加。此外，先前的研究表明，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的微出血。该提案首先旨在评估患有以下疾病的患者血浆 PLGF 是否上调：尸检神经病理学评估（目标 1a）中测量到的 SVD 病理学水平增加 PLGF 是否与人体组织中的 SVD 病理学具有紧密的空间共定位（目标 1b）。这将证明 PLGF 作为 SVD 病理学液体生物标志物的可行性。其次，我们会通过饮食来诱导在 PLGF-KO 转基因小鼠中建立完善的 VCID 模型，以评估 PLGF 对发育的作用微出血（目标 2）。这一目标将有助于支持我们的假设，即减少 PLGF 的可用性将减轻 SVD 患者的微出血负担。然后可以使用该机制来开发旨在阻止 VCID 进展的新疗法。通过这一提议并在 Sanders-Brown 老龄化中心的 Wilcock 博士和 Jicha 博士，申请人将研究 PLGF 的效用作为 SVD 的可修改液体生物标志物。在此过程中，申请人将接受基于免疫分析的培训生物标志物发现、统计线性模型、临床患者评估、免疫组织化学、病理学组织学评估以及口头和书面科学交流，为未来的独立职业生涯提供帮助医生科学家。