Pathophysiology of anti-B2GPI Antibodies in APS

描述（由申请人提供）：在申请指导研究科学家发展奖时，主要研究者要求在查佩尔山的北卡罗来纳州大学病理学教授Susan Lord博士和医学副教授Robert Roubey博士的监督下支持一项强化培训计划。本提案的目的是加强申请人在凝血和细胞生物学的生物化学基础方面的科学背景。如果获得资助，该奖项将促进申请人在止血和血栓形成领域发展独立科研事业的长期目标。候选人和她的导师已经制定了一个职业发展计划，其中包括：a）保证100%的受保护的研究时间，B）培训计划，使候选人接触生物化学，生物学和医学科学研究的新领域，以及c）研究生水平的研究，以加强实验室经验。 本申请中提出的研究将扩展申请人之前在止血和血栓形成研究方面的工作。与原发性抗磷脂综合征（APS）相关的静脉血栓形成的患病率可能高达一般人群的0.3%至1%，可能使APS成为最常见的自身免疫性疾病之一。假设针对血浆蛋白B2 GPI的抗体参与该疾病的发病机制。膜联蛋白A2最近被鉴定为B2 GPI的细胞受体。为了研究抗B2 GPI抗体的生物学和细胞相互作用，将解决以下具体目标：1）确定膜联蛋白A2是否介导抗B2 GPI抗体调节的TF活性表达，2）确定膜联蛋白A2介导的纤维蛋白溶解活性是否受B2 GPI或B2 GPI/抗B2 GPI调节，和3）确定APS自身抗体是否改变纤维蛋白凝块的结构和纤维蛋白溶解敏感性。预计这些拟议的研究将有助于对APS中血栓形成的致病机制的基本理解，并导致未来对APS治疗干预的研究。

DESCRIPTION (provided by applicant): In applying for the Mentored Research Scientist Development Award, the principal investigator is requesting support for an intensive program of training under the supervision of Dr. Susan Lord, Professor of Pathology, and Dr. Robert Roubey, Associate Professor of Medicine, at the University of North Carolina at Chapel Hill. The objectives of this proposal are designed to strengthen the applicant's scientific background in the biochemical basis of coagulation and cell biology. The award, if funded, will facilitate the long-term goals of the applicant in developing an independent scientific research career in the field of hemostasis and thrombosis. The Candidate and her mentors have developed a career development plan which includes: a) assurance of protected research time of 100 %, b) a training program exposing the Candidate to new areas of scientific investigation in biochemistry, biology and medicine, and c) graduate level studies to reinforce the laboratory experience. The studies proposed in this application will extend the applicant's previous work in hemostasis and thrombosis research. The prevalence of venous thrombosis associated with the primary Antiphospholipid Syndrome (APS) may be as high as 0.3 to 1% of the general population, possibly making APS one of the most common autoimmune diseases. It is hypothesized that antibodies against the plasma protein B2GPI are involved in the pathogenesis of this disease. Annexin A2 has recently been identified as the cellular receptor for B2GPI. To study the biological and cellular interactions of anti-B2GPI antibodies, the following specific aims will be addressed: 1) Determining whether annexin A2 mediates anti-B2GPI antibody-regulated expression of TF activity, 2) Determining whether annexin A2-mediated fibrinolytic activity is regulated by B2GPI or B2GPI/anti-B2GPI, and 3) Determining whether APS autoantibodies alter the structure and fibrinolytic susceptibility of the fibrin clot. It is expected that these proposed studies will contribute to a fundamental understanding of pathogenic mechanisms for thrombosis in APS and lead to future investigations addressing therapeutic interventions in APS.