PATHOGENESIS OF THROMBOSIS IN HIT

在申请导师临床医生科学家发展奖时， 首席调查员正在请求支持一项密集的计划 在沃尔特·基赛尔博士的监督下进行实验室培训， 新墨西哥大学健康科学分校病理学教授 中心。这项提案的目标旨在加强 申请人在生物化学基础方面的科学背景 凝血和内皮细胞生物学，这是一个 了解人类血栓性疾病。该奖项如果得到资助，将 促进申请者制定长期目标 在止血和血栓形成领域的独立科学生涯 医药。这位候选人和她的导师已经发展了自己的事业 发展计划，包括a)保证受保护的研究时间 80%-90%的b)培训计划使候选人接触到新的 生物化学、血管生物学、 黏附受体和脊椎动物生物学c)研究生水平的研究 加强实验室经验和d)一个咨询小组 资深调查人员，具有与 求婚。 本申请书中提出的研究将延长申请人的 肝素诱导的血小板减少症(HIT)和血栓形成的研究 (希特人)10%-20%的患者会发生危及生命的血栓 谁发展了Hit。HIT遗体中血栓形成的发病机制 不确定。与大多数其他免疫介导性血小板减少症不同 疾病，对内皮细胞的抗体可以在 命中/命中。推测同时存在的血小板和内皮细胞 细胞活化是血栓形成的关键。 易感人群。研究其生物学基础 血栓形成在HIT中发生，将研究以下具体目标： 1)表征HITT抗体与内皮细胞的相互作用 细胞。2)确定HITT血栓形成的生物学基础 小鼠模型。3)制备抗人免疫球蛋白单抗 PF4/肝素及其单抗的功能鉴定 尊重血栓形成。预计这些拟议的研究将 有助于从根本上理解糖尿病的发病机制 HITT的血栓形成，并导致未来的研究解决 HITT中的治疗干预。

In applying for the mentored clinician scientist development award, the principal investigator is requesting support for an intensive program of laboratory training under the supervision of Dr. Walter Kisiel, Professor of Pathology at the University of New Mexico Health Sciences Center. The objectives of this proposal are designed to strengthen the applicant's scientific background in the biochemical basis of coagulation and endothelial cell biology, areas essential for an understanding of human thrombotic disorders. The award, if funded, will facilitate the long-term goals of the applicant in developing an independent scientific career in the field of hemostasis and thrombosis medicine. The Candidate and her mentor have developed a career development plan which includes a) assurance of protected research time of 80-90 percent b) a training program exposing the Candidate to new areas of scientific investigation in biochemistry, vascular biology, adhesion receptors, and vertebrate biology c) graduate level studies to reinforce the laboratory experience and d) an advisory panel of established investigators with expertise in disciplines related to the proposal. The studies proposed in this application will extend the applicant's previous work on Heparin-induced Thrombocytopenia (HIT) and Thrombosis (HITT). Life-threatening thromboses occurs in 10-20 percent of patients who develop HIT. The pathogenesis of thrombosis in HIT remains uncertain. Unlike most other immune mediated thrombocytopenic disorders, antibodies to endothelial cells can be demonstrated in HIT/HITT. It is hypothesized that concurrent platelet and endothelial cell activation is critical for the development of thromboses in susceptible individuals. To study the biological basis by which thrombosis develops in HIT, the following specific aims will be studied: 1) Characterizing the interactions of HITT antibodies with endothelial cells. 2) Defining the biological basis of thrombosis in HITT using murine models. 3) Generation of monoclonal antibodies (MoAbs) to PF4/heparin and functional characterization of PF4/heparin MoAbs with respect to thrombosis. It is expected that these proposed studies will contribute to a fundamental understanding of pathogenetic mechanisms for thrombosis in HITT, and lead to future investigations addressing therapeutic interventions in HITT.