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Association of TFPI with antemortem dementia and postmortem micro brain infarcts

TFPI 与生前痴呆和死后微脑梗死的关联

基本信息

批准号：
8703779
负责人：
Susan Antone Maroney
金额：
$ 12.27万
依托单位：
VERSITI WISCONSIN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-19 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703779
关键词：
Affect Age Aging Alzheimer&apos s Disease American Anticoagulants Antigens Apolipoprotein E Asians Automobile Driving Autopsy Binding Biochemical Biological Blood Platelets Blood Vessels Blood coagulation Brain Brain Pathology Cardiovascular Diseases Cerebrum Clinical Coagulants Coagulation Process DNA Data Databases Deep Vein Thrombosis Dementia Deposition Development Disease E protein Employee Strikes Endothelial Cells Endothelium Enrollment Event Exons Factor Xa Family Fibrin Financial cost Genes Genetic Polymorphism Genotype Heart Histopathology Human Individual Infarction Intravascular Thrombus Formation Japanese American Japanese Population Laboratories Lead Linear Regressions Lipoprotein Binding Lipoproteins Logistic Regressions Low-Density Lipoproteins Lung Measurement Measures Memory Loss Modeling Mus National Heart, Lung, and Blood Institute Nucleic Acid Regulatory Sequences Organ Pathogenesis Pathology Patients Peptide Hydrolases Physiological Plasma Plasma Proteins Population Prevalence Promoter Regions Protein S Protein S Deficiency Proteins Reaction Risk Risk Factors Sampling Severities Specimen Structural Genes System TFPI Techniques Test Result Thrombin Thromboplastin Thrombosis Time Translating United States Variant Vascular Dementia apolipoprotein E-4 base cognitive function cohort human disease in utero inhibitor/antagonist innovation interest men mouse model novel prevent programs repository vascular factor

项目摘要

DESCRIPTION (provided by applicant): In 2001, the world wide number of patients with dementia was approximately 24 million and is expected to increase to 84 million people by the year 2040. Vascular factors appear to be a major component to dementia including those factors involving coagulation. Tissue Factor Pathway Inhibitor (TFPI) is the primary physiological inhibitor of tissue factor, the initiator of clotting after a blood vessel has been damaged, and FXa, a major component of the clotting system that produces a large amount of thrombin resulting in clot formation. TFPI is found in endothelial cells, in platelets or in plasma. In plasa it is either bound to the plasma lipoproteins, predominately LDL, with less anti-coagulant activity or in an active free unbound form. Another anti-coagulant protein, Protein S (PS), directly interacts with TFPI promoting an enhanced inhibition of FXa. Mouse models of either tfpi-/- and pros-/- mice die in utero and have intravascular fibrin clots in the brain. Normal variations in plasma TFPI and PS concentrations are strongly influenced by polymorphisms in their respective structural genes. Several TFPI polymorphisms and PS polymorphisms have been associated with deep vein thrombosis, however, it is not known if polymorphisms of these two interactive proteins cause micro- brain infarcts and dementia. Preliminary data demonstrate that mouse models lacking either endothelial cell or platelet TFPI produce intravascular fibrin micro-clots preferentially in the brain suggesting a critical amount of TFPI and /or PS are necessary to prevent abnormal clotting in the brain. We have techniques available within our laboratory to translate the data from mouse models to the disease of human dementia using DNA and plasma specimens from the NHLBI BioLINCC Honolulu Heart Project consisting of a homogenous population of Japanese and Japanese-Americans residing in Honolulu. Of interest are the 404 individuals with and without dementia who later came to autopsy in which brain pathology was characterized. In Aim1 we will sequence the exons and 5' promoter region of the TFPI gene in all individuals to identify any polymorphisms and correlate the polymorphisms with TFPI plasma concentrations and anti-FXa activity. In Aim2 we will identify individuals with the PS 196K>E polymorphism which is found uniquely in the Japanese population and correlate this polymorphism with the PS plasma concentration and anti-thrombotic activity. In Aim3 we will correlate the TFPI plasma concentrations and activity with lipoprotein levels and ApoE genotype of the cohort which have been previously determined. At the conclusion of these studies, we will have identified TFPI polymorphisms associated with dementia and determined the TFPI plasma concentrations and activity with the polymorphisms, determined the relationship of the 196K>E PS polymorphism to dementia and correlated the associated plasma concentration and activity of PS with dementia, and determined the relationship of TFPI to ApoE. Finally, other risk factors of cardiovascular disease found within the BioLINCC database will be used in a linear regression model to determine the significance of TFPI and PS on the pathogenesis of dementia.

描述（由申请人提供）：2001年，全世界痴呆症患者人数约为2400万，预计到2040年将增加到8400万。血管因素似乎是痴呆症的主要组成部分，包括那些涉及凝血的因素。组织因子途径抑制剂 (TFPI) 是组织因子和 FXa 的主要生理抑制剂，组织因子是血管受损后凝血的引发剂，FXa 是凝血系统的主要成分，可产生大量凝血酶，导致血栓形成。 TFPI 存在于内皮细胞、血小板或血浆中。在血浆中，它与血浆脂蛋白（主要是低密度脂蛋白）结合，抗凝血活性较低或处于活性的游离非结合形式。另一种抗凝血蛋白 Protein S (PS) 直接与 TFPI 相互作用，促进 FXa 的增强抑制。 tfpi-/- 和 pro-/- 小鼠模型均会在子宫内死亡，并且大脑中出现血管内纤维蛋白凝块。血浆 TFPI 和 PS 浓度的正常变化受到各自结构基因多态性的强烈影响。几种 TFPI 多态性和 PS 多态性已与深静脉血栓形成相关，然而，尚不清楚这两种相互作用蛋白的多态性是否会导致微脑梗塞和痴呆。初步数据表明，缺乏内皮细胞或血小板 TFPI 的小鼠模型优先在大脑中产生血管内纤维蛋白微凝块，这表明需要大量的 TFPI 和/或 PS 来防止大脑中的异常凝血。我们实验室拥有可用的技术，可以使用 NHLBI BioLINCC 檀香山心脏项目（由居住在檀香山的日本人和日裔美国人的同质人群组成）的 DNA 和血浆样本，将小鼠模型的数据转化为人类痴呆症。令人感兴趣的是 404 名患有或未患有痴呆症的人，他们后来进行了尸检，并在尸检中对大脑病理进行了表征。在 Aim1 中，我们将对所有个体的 TFPI 基因的外显子和 5' 启动子区域进行测序，以识别任何多态性，并将多态性与 TFPI 血浆浓度和抗 FXa 活性相关联。在 Aim2 中，我们将鉴定具有在日本人群中独特发现的 PS 196K>E 多态性的个体，并将这种多态性与 PS 血浆浓度和抗血栓活性相关联。在 Aim3 中，我们将 TFPI 血浆浓度和活性与先前确定的队列的脂蛋白水平和 ApoE 基因型相关联。在这些研究结束时，我们将鉴定与痴呆相关的 TFPI 多态性，并确定多态性的 TFPI 血浆浓度和活性，确定 196K>E PS 多态性与痴呆的关系，并将 PS 的血浆浓度和活性与痴呆相关，并确定 TFPI 与 ApoE 的关系。最后，BioLINCC 数据库中发现的其他心血管疾病危险因素将用于线性回归模型，以确定 TFPI 和 PS 对痴呆发病机制的重要性。