Association of TFPI with antemortem dementia and postmortem micro brain infarcts

描述（由申请人提供）：2001年，全世界痴呆症患者的数量约为2400万，预计到2040年将增加到8400万。血管因素似乎是痴呆的主要组成部分，包括涉及凝血的那些因素。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是凝血系统的主要组分，其产生大量凝血酶，导致凝块形成。TFPI存在于内皮细胞、血小板或血浆中。在血浆中，它要么与血浆脂蛋白结合，主要是LDL，抗凝血活性较低 或以活性自由未结合形式存在。另一种抗凝蛋白，蛋白S（PS），直接与TFPI相互作用，促进FXa的抑制增强。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凝块。血浆TFPI和PS浓度的正常变化受到其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引起微脑梗死和痴呆。初步数据表明，缺乏内皮细胞或血小板TFPI的小鼠模型优先在脑中产生血管内纤维蛋白微凝块，这表明临界量的TFPI和/或PS是防止脑中异常凝血所必需的。我们的实验室内有技术可利用NHLBI BioLINCC檀香山心脏项目的DNA和血浆样本将小鼠模型的数据转化为人类痴呆症的疾病，该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。令人感兴趣的是404名患有和没有痴呆症的人，他们后来进行了尸检，其中大脑病理学的特点。在Aim 1中，我们将对所有个体的TFPI基因的外显子和5'启动子区进行测序，以鉴定任何多态性，并将多态性与TFPI血浆浓度和抗FXa活性相关联。在Aim 2中，我们将鉴定具有PS 196 K>E多态性的个体，该多态性在日本人群中唯一发现，并将该多态性与PS血浆浓度和抗血栓形成活性相关联。在Aim 3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。在这些研究的结论中，我们将确定与痴呆相关的TFPI多态性，并确定TFPI血浆浓度和活性与多态性，确定196 K>E PS多态性与痴呆的关系，并确定相关的血浆浓度和活性的PS与痴呆，并确定TFPI与ApoE的关系。最后，在BioLINCC数据库中发现的心血管疾病的其他危险因素将用于线性回归模型，以确定TFPI和PS对痴呆发病机制的意义。

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.