Platelet-hyaluronan interactions as regulators of inflammation and thrombosis

血小板-透明质酸相互作用作为炎症和血栓形成的调节剂

• 批准号: 10080750
• 负责人: Aaron Christopher Petrey
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080750
• 关键词: Abnormal Platelet; Acute Lung Injury; Address; Animals; Atherosclerosis; Biochemical; Biochemistry; Biogenesis; Biology; Biomedical Research; Blood Platelets; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cells; Chronic; Coagulation Process; Colitis; Cues; Data; Defect; Deposition; Development; Development Plans; Disease; Effector Cell; Elements; Endothelium; Environment; Enzymes; Experimental Models; Extracellular Matrix; Foundations; Functional disorder; Funding; Future; Glycobiology; Glycosaminoglycans; Hemostatic function; Human; Hyaluronan; Hyaluronidase; Immune; Immune response; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Investigation; Leukocytes; Life; Mediating; Megakaryocytes; Mentors; Mentorship; Mission; Modeling; Molecular; Mus; National Heart, Lung, and Blood Institute; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Platelet Activation; Post-Translational Regulation; Postdoctoral Fellow; Prevention; Productivity; Proteins; Public Health; Recombinants; Records; Research; Research Personnel; Research Priority; Resources; Role; Sentinel; Sepsis; Severities; Severity of illness; Signal Transduction; Solid; Specimen; Structure; Surveys; Technical Expertise; Testing; Thrombosis; Tissues; Training; Transcriptional Regulation; Transfusion; Translating; Translational Regulation; Translational Research; base; career; career development; chronic inflammatory disease; human disease; inflammatory disease of the intestine; inflammatory marker; insight; lens; mouse model; novel; platelet function; pre-doctoral; programs; receptor binding; recruit; response; sensor; skills training; supportive environment; thromboinflammation; vascular factor

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.

项目总结