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: 10618978
• 负责人: Zachary Winder
• 金额: $ 3.23万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618978
• 关键词: Aging; Alzheimer' s Disease; Analysis of Covariance; Animal Model; Arterioloscleroses; 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; Hemorrhage; Histology; Human; Hyperhomocysteinemia; Hypoxia; Immunoassay; Immunohistochemistry; Impaired cognition; Infarction; Linear Models; Link; Liquid substance; Magnetic Resonance Imaging; Measures; Mediation; Mediator; 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; Writing; angiogenesis; biomarker discovery; brain tissue; burden of illness; candidate marker; career; cerebrovascular pathology; cohort; comparison control; 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 痴呆症是一种以一项或多项认知能力较基线显著下降为特征的障碍。 干扰独立性的领域。全球痴呆症患病率估计为5000万，其中 预计到2030年，这一数字将增加两倍，成本约为2万亿美元。对血管的贡献 认知障碍和痴呆症(VCID)是导致痴呆症的第二大原因，是总称 用于描述由于脑血管病变而导致的认知功能障碍的患者。小船 脑血管疾病(SVD)是一种脑血管病变，大约50%的VCID患者可以发现这种疾病。 与SVD相关的常见神经病理表现包括微梗塞、微出血和 小动脉硬化。虽然MRI可以识别更大的梗塞和微出血，但它受到扫描分辨率的限制。 因此，除了尸检评估外，这些病理组织的鉴定被证明是困难的。白质 磁共振高信号(WMH)已成为评价SVD的标准，但其成本受到限制 以及缺乏有针对性的机制来防止疾病的发展。在本提案中，我们探讨了 血管生成介质作为可修饰的流体生物标记物的作用，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，这是在动脉硬化中发现的。我们的初步数据显示，VCID患者 与对照组相比，PLGF浓度有所增加。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，这是形成的初始步骤 微小出血的迹象。这项建议首先试图评估血浆PLGF是否在慢性阻塞性肺疾病患者中表达上调 死后神经病理评估中测量的SVD病理水平升高(目标1a)和 PLGF在人体组织中是否与SVD病理有紧密的空间共定位(目标1b)。这将是 证明PLGF作为SVD病理的液体生物标记物的可行性。其次，我们将使用饮食来诱导 在PLGF-KO转基因小鼠中建立VCID模型，以评价PLGF在VCID发育中的作用 微量出血(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。然后可以使用这种机制来开发 新的治疗方法，以阻止VCID的进展。通过这项建议，并在 威尔科克博士和吉查博士在桑德斯-布朗老龄中心，申请人将调查PLGF的效用 作为SVD的可修改的流体生物标志物。在这样做的过程中，申请者将接受基于免疫分析的培训 生物标记物发现、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，以及未来独立职业生涯的口头和书面科学交流 医生兼科学家。

项目成果

Examining the association between blood-based biomarkers and human post mortem neuropathology in the University of Kentucky Alzheimer's Disease Research Center autopsy cohort.

在肯塔基大学阿尔茨海默病研究中心尸检队列中检查血液生物标志物与人类死后神经病理学之间的关联。

• DOI: 10.1002/alz.12639
• 发表时间: 2023
• 期刊: Alzheimer's & dementia : the journal of the Alzheimer's Association
• 作者: Winder,Zachary;Sudduth,TiffanyL;Anderson,Sonya;Patel,Ela;Neltner,Janna;Martin,BarbaraJ;Snyder,KatherineE;Abner,ErinL;Jicha,GregoryA;Nelson,PeterT;Wilcock,DonnaM
• 通讯作者: Wilcock,DonnaM