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Factor XIII and Fibrinogen: Mechanisms of Genetic Risk in SCD-Related Priapism

XIII 因子和纤维蛋白原：SCD 相关阴茎异常勃起的遗传风险机制

基本信息

批准号：
9107455
负责人：
Marilyn J Telen
金额：
$ 19.53万
依托单位：
DUKE UNIVERSITY
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：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9107455
关键词：
Acute Affect American Anticoagulation Biochemistry Biological Markers Blood Blood Cells Blood Platelets Blood Vessels Blood coagulation Cellular biology Clinical Coagulation Process Code Complication Confidence Intervals Corpora Cavernosa Data Disease Elements Erythrocytes Event Factor XIII Fibrin Fibrinogen Fibronectins Figs - dietary Frequencies Functional disorder General Population Genes Genetic Polymorphism Genetic Predisposition to Disease Genetic Risk Genotype Goals Health Impotence Individual Investigation Laminin Lead Leukocytes Measures Molecular Odds Ratio Pain Pathogenesis Pathway interactions Patients Penile Erection Plasma Plasma Proteins Play Prevention Priapism Process Proteins Recurrence Risk Role Sickle Cell Sickle Cell Anemia Thrombus Variant Venous Whole Blood crosslink effective therapy erection male new therapeutic target novel therapeutic intervention patient population penis prevent risk variant thrombolysis

项目摘要

DESCRIPTION (provided by applicant): Priapism affects between 30-40% of males with sickle cell disease (SCD). Priapism involves engorgement of penile vessels and blood stasis in these vessels, but the process underlying its pathogenesis remains unclear. Consequently, treatment for acute and recurrent priapism remains highly unsatisfactory. Recent efforts to explore genetic predisposition to priapism in SCD has resulted in the identification of several genetic polymorphisms associated with risk for priapism. Two of the most strongly associated polymorphisms reside in proteins in the coagulation cascade: the Factor XIII A-chain (FXIIIA) and the fibrinogen ß-chain. Notably, over 90% of SCD subjects with priapism have at least one risk genotype, suggesting that fibrin formation and fibrin(ogen) crosslinking play key roles in the pathophysiology of priapism in SCD. We hypothesize that these polymorphisms in FXIII and fibrinogen affect the risk for priapism in SCD by altering crosslinking of fibrin (or crosslinking f other proteins, such as fibronectin, to fibrin) and interactions of sickle RBCs with fibrin clots o with other cellular elements (i.e., other blood cells). To understand the mechanism responsible for the association of these polymorphisms with priapism in SCD, we propose two Specific Aims. Aim 1: Compare coagulation activation, fibrin crosslinking, capture of RBCs in clots and clot stability, in individuals with and without the FXIIIA and fibrinogen ß-chain polymorphisms associated with priapism. We hypothesize that SCD patients with FXIII and fibrinogen risk alleles will have a more rapid or pronounced degree of fibrin crosslinking, increased RBC retention in clots, and increased clot stability. We will also characterize changes in these measures during priapic episodes. Aim 2: Determine the effects of FXIIIA and fibrinogen ß-chain polymorphisms on the frequency and composition of circulating heterologous blood cell aggregates in SCD patients during steady state. We hypothesize that SCD patients with FXIII and fibrinogen risk alleles will have increased circulating heterocellular aggregates and increased FXIII substrates (e.g., fibrin, fibronectin or laminin) cross-linked in cellular aggregats. We expect that elucidating the mechanisms associating FXIII and fibrinogen polymorphisms with priapism risk in SCD will reveal pathophysiological processes leading to this devastating complication. We anticipate that this information will identify and allow investigation of new therapeutic targets.

描述（由申请人提供）：阴茎异常勃起影响30-40%的镰状细胞病（SCD）男性。阴茎异常勃起包括阴茎血管充血和这些血管中的血液淤滞，但其发病机制仍不清楚。因此，急性和复发性阴茎异常勃起的治疗仍然非常不令人满意。最近的努力，以探索遗传易感性，以阴茎异常勃起的SCD已导致在确定几个遗传多态性与阴茎异常勃起的风险。两种最强相关的多态性存在于凝血级联中的蛋白质中：因子XIII A链（FXIIIA）和纤维蛋白原β链。值得注意的是，超过90%的患有阴茎异常勃起的SCD受试者具有至少一种风险基因型，这表明纤维蛋白形成和纤维蛋白（原）交联在阴茎异常勃起中起关键作用。 SCD阴茎异常勃起的病理生理学我们假设FXIII和纤维蛋白原中的这些多态性通过改变纤维蛋白的交联（或其他蛋白质如纤连蛋白与纤维蛋白的交联）和镰状RBC与纤维蛋白凝块或与其他细胞成分（即，其他血细胞）。为了了解这些多态性与SCD阴茎异常勃起相关的机制，我们提出了两个具体目标。目标1：比较伴有和不伴有与阴茎异常勃起相关的FXIIIA和纤维蛋白原β链多态性的个体的凝血激活、纤维蛋白交联、血凝块中RBC捕获和血凝块稳定性。我们假设，具有FXIII和纤维蛋白原危险等位基因的SCD患者将具有更快或更显著的纤维蛋白交联程度，增加血凝块中RBC滞留，并增加血凝块稳定性。我们还将描述阴茎异常勃起发作期间这些措施的变化。目标二：确定FXIIIA和纤维蛋白原β-链多态性对稳态期间SCD患者循环异源血细胞聚集体的频率和组成的影响。我们假设具有FXIII和纤维蛋白原风险等位基因的SCD患者将具有增加的循环异细胞聚集体和增加的FXIII底物（例如，纤维蛋白、纤连蛋白或层粘连蛋白）在细胞聚集体中交联。我们希望阐明FXIII和纤维蛋白原多态性与SCD阴茎异常勃起风险相关的机制，将揭示导致这种毁灭性并发症的病理生理过程。我们预计，这些信息将确定并允许新的治疗靶点的调查。