Pathophysiology of anti-B2GPI Antibodies in APS

描述(由申请人提供)：在申请导师研究科学家发展奖时，首席研究员请求支持北卡罗来纳大学教堂山分校病理学教授苏珊·洛德博士和医学副教授罗伯特·鲁贝博士指导下的强化培训计划。这项建议的目的是为了加强申请人在凝血和细胞生物学的生化基础方面的科学背景。该奖项如果获得资助，将有助于申请者在止血和血栓形成领域发展独立的科学研究事业的长期目标。候选人和她的导师已经制定了职业发展计划，其中包括：a)保证100%的受保护研究时间，b)培训计划，让候选人接触到生物化学、生物和医学的新科学研究领域，以及c)研究生水平的学习，以加强实验室经验。 本申请中提出的研究将扩展申请人先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)相关的静脉血栓的患病率可能高达普通人群的0.3%至1%，可能使APS成为最常见的自身免疫性疾病之一。推测抗血浆蛋白B2GPI抗体参与了本病的发病机制。膜联蛋白A2最近被确定为B2GPI的细胞受体。为了研究抗B2GPI抗体的生物和细胞相互作用，将解决以下特定目的：1)确定Annexin A2是否介导抗B2GPI抗体调节的TF活性的表达；2)确定Annexin A2介导的纤溶活性是否受B2GPI或B2GPI/抗B2GPI调节；以及3)确定APS自身抗体是否改变纤维蛋白凝块的结构和纤溶敏感性。预计这些拟议的研究将有助于从根本上了解APS血栓形成的发病机制，并导致未来针对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.