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：
8466410
负责人：
Susan Antone Maroney
金额：
$ 12.53万
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8466410
关键词：
Affect Age Aging Alzheimer&apos s Disease American Anticoagulants Antigens Apolipoprotein E Asians Automobile Driving Autopsy Binding Biochemical Biological Blood Clot 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，全球痴呆症患者约为2400万，预计到2040年将增加到8400万人。血管因素似乎是痴呆症的主要成分，包括涉及凝血的因素。组织因子途径抑制剂（TFPI）是组织因子的主要生理抑制剂，是血管后凝结后的凝结剂的引发剂，FXA是凝结系统的主要成分，它会产生大量的凝血酶，从而导致凝块形成。在内皮细胞，血小板或血浆中发现TFPI。在质量中，它要么与血浆脂蛋白结合，主要是LDL，具有较少的抗凝活性或以主动的自由未结合形式。另一种抗凝蛋白蛋白S（PS）直接与TFPI相互作用，促进了FXA的抑制作用。 TFPI - / - 和Pros - / - 小鼠的小鼠模型在子宫内死亡，并且在大脑中具有血管内纤维蛋白血块。血浆TFPI和PS浓度的正常变化受其各自结构基因中多态性的强烈影响。几种TFPI多态性和PS多态性与深静脉血栓形成有关，但是，尚不清楚这两种互动蛋白的多态性是否引起微脑梗塞和痴呆。初步数据表明，缺乏内皮细胞或血小板TFPI的小鼠模型在大脑中优先产生血管内纤维蛋白微斑点，这表明TFPI和 /或PS的关键量对于防止大脑异常凝结是必要的。我们在实验室内有可用的技术，可以使用NHLBI Biolincc檀香山心脏项目的DNA和血浆标本将数据从小鼠模型转换为人类痴呆症，该数据由居住在檀香山的日本和日裔美国人组成。感兴趣的是404名患有和没有痴呆症的人，后来尸检对脑病理学的表征进行了尸检。在AIM1中，我们将在所有个体中的TFPI基因的外显子和5'启动子区域进行鉴定，以鉴定任何多态性，并将多态性与TFPI血浆浓度和抗FXA活性相关。在AIM2中，我们将确定具有PS 196K> e多态性的个体，这在日本人群中独特地发现，并将这种多态性与PS血浆浓度和抗栓性活性相关。在AIM3中，我们将将TFPI血浆浓度和活性与脂蛋白水平以及先前已经确定的脂蛋白水平和APOE基因型相关联。在这些研究的结论下，我们将确定与痴呆相关的TFPI多态性，并确定了TFPI血浆浓度和与多态性的活性，确定了196K> e PS多态性与痴呆与痴呆与痴呆的关系，并与PS的相关等离子浓度和活性相关，并确定了PS与dementia的相关浓度和活性与TFPI的关系。最后，在线性回归模型中将使用在生物林克数据库中发现的心血管疾病的其他危险因素，以确定TFPI和PS对痴呆发病机理的重要性。