Platelet-hyaluronan interactions as regulators of inflammation and thrombosis

项目总结 标题：作为炎症和血栓形成调节剂的血小板-透明质酸相互作用 关键词：血小板、透明质酸、炎症、血栓形成、透明质酸酶-2 该候选人是一名博士后研究员和致力于发展学术事业的年轻研究员。 专注于通过细胞外基质晶状体研究炎症和血栓形成的交集 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，应聘者在机械血小板生物学和 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2年的指导性培训，包括技术技能培训和职业发展活动，以 促进向独立和未来供资的成功过渡。候选人的导师和共同导师 拥有卓越的翻译研究效率和成功的指导经验。研究 计划：血小板是止血所必需的特殊细胞，也是关键的效应器，能够 调节炎症和免疫反应。这些与生俱来的免疫感应器不断地探测它们的 并区分动态平衡信号和危险信号。细胞外基质的成分 (ECM)被血小板检测为“损伤相关分子模式”(DAMPS)，并可诱发亲和性。 炎症反应。一种这样的细胞外基质成分，糖胺聚糖透明质酸(HA)，获得了一种独特的 对炎症作出反应的“索状”结构。我们的实验室已经证明：(1)HA电缆的形成先于 炎性细胞浸润，(2)内皮细胞产生的HA电缆募集白细胞，(3)需要Hyal-2 用于血小板生物生成，以及(4)血小板衍生酶Hyal-2降解HA电缆。我们的预赛 观察表明，系统性Hyal-2缺乏的小鼠表现出炎症和疾病的增加 结肠炎小鼠模型的严重程度。重要的是，这些发现通过输注野生- 血型：血小板。我们认为，这些结果翻译了一种全新的机制，通过这种机制，血小板-HA 相互作用调节炎症，并将提供对炎症途径的新见解，可概括为 其他炎症性疾病。根据我们的初步数据，我们提出了一个重要的假设： 由于血小板Hyal-2缺乏导致的血管透明质酸调节失调会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， 炎症可以改变巨核细胞发育和血小板的潜在机制 通过使用独特的患者来源标本和小鼠炎症模型的生物发生。这 应用程序建立在强大的初步数据基础上，个人富有成效的研究记录， 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咨询小组， 血栓形成，转化性研究，以及一个全身心投入的部门。这些元素加在一起将支持 并促进PI的培训和晋升，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.