Platelet-hyaluronan interactions as regulators of inflammation and thrombosis

项目摘要 标题：血小板-透明质酸相互作用作为炎症和血栓形成的调节剂 关键词：血小板，透明质酸，炎症，血栓形成，透明质酸酶-2 候选人是一名博士后研究员和年轻的研究员，致力于发展学术生涯 专注于通过细胞外基质透镜研究炎症和血栓形成的交叉点， 慢性炎症性疾病的潜在机制。有很强的细胞外基质背景 生物学和生物化学，该候选人在机械血小板生物学和生物化学方面积累了新的专业知识 使用小鼠模型进行拟议的研究。建议书中描述的职业发展计划 概述了2年的指导培训，包括技术技能培训和职业发展活动， 促进向独立的成功过渡和今后的供资。候选人的导师和共同导师 具有卓越的，转化研究生产力和成功的指导证明的跟踪记录。研究 计划：血小板是对止血至关重要的特化细胞，也是能够 调节炎症和免疫反应。这些先天免疫传感器不断地检测它们的 环境和区分稳态和危险信号。细胞外基质的组分 (ECM)被血小板检测为“损伤相关分子模式”（DAMPS），并可引起促血小板生成素（Pro- 炎症反应。一种这样的ECM组分，糖胺聚糖透明质酸（HA），获得独特的生物活性。 对炎症反应的“索状”结构。我们的实验室已经表明：（1）HA电缆的形成先于 炎症细胞浸润，（2）内皮细胞产生的HA电缆募集白细胞，（3）需要Hyal-2 用于血小板生物发生，以及（4）血小板衍生酶Hyal-2降解HA电缆。我们的初步 观察显示，具有系统性Hyal-2缺陷的小鼠显示增加的炎症和疾病 严重程度的小鼠模型的结肠炎。重要的是，这些发现显着减少输血的野生型- 型血小板。我们相信这些结果解释了一种全新的机制， 相互作用调节炎症，并将为炎症途径提供新的见解， 其他炎症性疾病。根据我们的初步数据，我们提出了一个总体假设： 由于血小板Hyal-2缺乏引起的血管HA调节异常促进炎症和血栓形成。 我们将评估血小板-透明质酸相互作用调节炎症、血栓形成 以及炎症改变巨核细胞发育和血小板聚集的潜在机制。 通过使用患者来源的标本和小鼠炎症模型的独特资源，这 应用程序建立在强大的初步数据，个人的生产性研究记录， 支持性环境，一个因其在炎症方面的专业知识而获得国家认可的顾问小组， 血栓形成和转化研究，以及一个完全致力于的部门。这些因素将共同支持 并促进PI的培训和发展，使其成为独立生物医学研究的成功职业。

PROJECT SUMMARY Title: Platelet-hyaluronan interactions as regulators of inflammation and thrombosis Key Words: Platelets, hyaluronan, inflammation, thrombosis, Hyaluronidase-2 The Candidate is a postdoctoral fellow and young investigator dedicated to developing an academic career focused on investigating the intersection of inflammation and thrombosis through an extracellular matrix lens as an underlying mechanism in chronic inflammatory disease. With a strong background in extracellular matrix biology, and biochemistry, the candidate has developed new expertise in mechanistic platelet biology and the use of mouse models to conduct the proposed studies. The Career Development Plan described in the proposal outlines 2 years of mentored training including technical skill training and career development activities to promote the successful transition to independence and future funding. The candidate's Mentor and Co-Mentor have proven track-records of excellent, translational research productivity and successful mentorship. Research Plan: Platelets are specialized cells essential for hemostasis that also function as crucial effectors capable of modulating inflammatory and immune responses. These innate immune sensors continually survey their environment and discriminate between homeostatic and danger signals. Components of the extracellular matrix (ECM) are detected by platelets as `damage associated-molecular patterns' (DAMPS) and can elicit pro- inflammatory responses. One such ECM component, the glycosaminoglycan hyaluronan (HA), acquires a unique `cable-like' structure in response to inflammation. Our lab has shown that: (1) HA cable formation precedes inflammatory cell infiltration, (2) HA cables produced by the endothelium recruit leukocytes, (3) Hyal-2 is required for platelet biogenesis, and (4) the platelet-derived enzyme Hyal-2 degrades HA cables. Our preliminary observations show that mice with systemic Hyal-2 deficiency display increased inflammation and disease severity in a murine model of colitis. Importantly, these findings are significantly reduced by transfusion of wild- type platelets. We believe that these results translate an entirely new mechanism by which platelet-HA interactions regulate inflammation and will provide new insights into inflammatory pathways generalizable to other inflammatory diseases. Based on our preliminary data we propose the overarching hypothesis that: Dysregulation of vascular HA due to platelet Hyal-2 deficiency promotes inflammation and thrombosis. We will evaluate the mechanism(s) by which platelet-hyaluronan interactions regulate inflammation, thrombosis, and the underlying mechanism in which inflammation can alter megakaryocyte development and platelet biogenesis by using a unique resource of patient-derived specimens and mouse models of inflammation. This application builds on robust preliminary data, a personal track record of productive research, an extremely supportive environment, an advisory panel with national recognition for their expertise in inflammation, thrombosis, and translational research, and a fully committed department. Together these elements will support and facilitate the training and advancement of the PI to a successful career of independent biomedical research.