Novel lipoprotein particles, brain abnormalities, and risk of dementia and stroke

新型脂蛋白颗粒、大脑异常以及痴呆和中风的风险

基本信息

批准号：
9272957
负责人：
Majken Karoline Jensen
金额：
$ 62.94万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272957
关键词：
Abeta clearance Affect Alzheimer&apos s Disease American Amyloid beta-Protein Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein E Apolipoproteins Apolipoproteins A Apoptosis Apoptotic Behavior Biochemistry Biological Assay Biological Markers Brain Budgets Cardiovascular Diseases Carrier Proteins Cerebrospinal Fluid Cerebrum Cholesterol Clinical Dementia Deposition Development Diabetes Mellitus Early Diagnosis Enzyme-Linked Immunosorbent Assay Enzymes Evaluation Family Ginkgo biloba Government Healthcare Healthcare Systems High Density Lipoprotein Cholesterol High Density Lipoproteins Human Impaired cognition Individual Infarction Institutionalization Investigation Knowledge Laboratories Late Onset Alzheimer Disease Lead Lipids Lipoproteins Low-Density Lipoproteins Magnetic Resonance Imaging Measures Mediating Mediator of activation protein Memory Metabolism Mission Monitor Nerve Degeneration Neurocognitive Neurology Participant Pathogenesis Pittsburgh Compound-B Plasma Positron-Emission Tomography Prevalence Prevention Prevention strategy Prospective Studies Proteins Public Health Research Risk Risk Factors Risk Marker Risk stratification Role Sampling Stroke Stroke prevention Testing Therapeutic Agents United States National Institutes of Health Variant Work apolipoprotein E-4 aqueous base brain abnormalities cardiovascular disorder risk cardiovascular health cerebral atrophy cognitive function density disability disorder risk early detection biomarkers genetic risk factor genome wide association study genome-wide analysis improved innovation laboratory equipment minimally invasive molecular pathology nervous system disorder new technology new therapeutic target novel novel marker particle prospective protein transport public health relevance receptor tool

项目摘要

DESCRIPTION (provided by applicant): Dementia and stroke are increasing in prevalence. These neurological diseases are major causes of disability and institutionalization and place a crushing burden on individuals, caretakers and the government's healthcare budget. There is an unmet need for the discovery of novel markers that may be used for early detection, prevention, and point toward potential development of novel targets for therapeutics. Some of the strongest known risk factors for dementia and stroke are related to apolipoproteins, a broad class of proteins that transport a variety of compounds in aqueous solutions like the cerebrospinal fluid (CSF) and plasma. The apoE4 variant is the single strongest known risk factor for late onset Alzheimer's disease (AD), and recently apoJ was also identified in genome-wide association studies of AD. Other apolipoproteins, such as apoAI and apoCIII are also found in CSF, even though they aren't expressed there. Apolipoproteins determine the function and metabolism of lipoproteins (HDL and LDL) by mediating their interaction with receptors and enzymes. Thus far, the role of apolipoproteins in neurological disease has only been studied in a crude manner, and it has not yet been considered that apoE is found on both HDL and LDL; two lipoproteins with opposing associations with dementia and stroke. Further, it has not been examined whether the inverse association of HDL with stroke and dementia is attributable to its apoE content. The overall objective of this proposal is to investigate plasma apolipoprotein-defined HDL subspecies as novel risk markers for neurological disease. Our central hypothesis is that apolipoproteins of demonstrated importance to brain cholesterol and beta-amyloid (Ab) metabolism (apoJ, apoE and apoCIII) may identify subspecies of HDL that are more closely involved in the pathogenesis. In our laboratory we have developed a novel ELISA assay that can assess HDL subspecies according to apolipoprotein content. We have found that in contrast to the protective associations of total HDL and HDL without apoCIII, HDL with apoCIII lacks a beneficial association with diabetes and cardiovascular disease risk. We wish to leverage our proven laboratory technology to investigate HDL subspecies, defined on the basis of apoE, apoJ and apoCIII, in association with risk of dementia, stroke, cognitive decline, Ab deposition, and brain atrophy. In this project we will combine two research fields (lipoprotein biochemistry and neurology) in an innovative way to discover novel HDL subspecies that may contain more value for risk prediction than the traditionally used clinical measures of HDL-cholesterol. Our rationale for the proposed research is that apolipoprotein-defined HDL subspecies likely capture the functional correlates of HDL rather than just its average cholesterol concentration. We expect that the investigations of these minimally invasive plasma measures may lead to improved risk stratification and prevention.

描述（由应用程序提供）：痴呆和中风的患病率正在增加。这些神经系统疾病是造成混乱和制度化的主要原因，并对个人，看护人和政府的医疗保健预算造成了严重的烧伤。发现新的标记物的需求未满足，这些标记物可能用于早期检测，预防和指向潜在的新靶标的治疗目标。痴呆和中风的一些强烈危险因素与载脂蛋白有关，载脂蛋白是一种广泛的蛋白质，它们在脑脊液（CSF）和血浆等水溶液中运输各种化合物。 APOE4变体是晚期发病（AD）的最强的已知危险因素，最近在全基因组关联研究中也发现了APOJ。 CSF中也发现了其他载脂蛋白，例如ApoaI和Apocii，即使在那里没有表达。载脂蛋白通过介导其与受体和酶的相互作用来确定脂蛋白（HDL和LDL）的功能和代谢。远处的载脂蛋白在神经系统疾病中的作用仅以粗略的方式进行了研究，尚未被认为是在HDL和LDL上发现ApoE。两种与痴呆和中风相反的脂蛋白。此外，尚未研究HDL与中风和痴呆的逆关联是否归因于其APOE含量。该提案的总体目的是研究血浆载脂蛋白定义的HDL亚种作为神经系统疾病的新风险标志物。我们的中心假设是，对脑胆固醇和β-淀粉样蛋白（AB）代谢（APOJ，APOE和APOCIII）具有重要意义的载脂蛋白可能会鉴定HDL的亚种更紧密地参与病原体。在我们的实验室中，我们开发了一种新型的ELISA分析，可以根据载脂蛋白含量评估HDL亚种。我们发现，与没有Apocii的总HDL和HDL的受保护关联相反，HDL与Apocii缺乏与糖尿病和心血管疾病风险的有益关联。我们希望利用我们久经考验的实验室技术来研究基于APOE，APOJ和APOCIII的基础定义的HDL亚种，并与痴呆症，中风，认知能力下降，AB沉积和脑萎缩的风险相关。在该项目中，我们将以一种创新的方式结合两个研究领域（脂蛋白生物化学和神经病学），以发现与传统使用的HDL-胆固醇的临床指标相比，这些新型HDL亚种可能具有更多的风险预测价值。我们对拟议的研究的理由是，载脂蛋白定义的HDL亚种可能捕获了HDL的功能相关性，而不仅仅是其平均胆固醇浓度。我们预计对这些微创等离子体测量的研究可能会改善风险分层和预防。