Platelet Activation and Inflammatory Mediators

血小板激活和炎症介质

• 批准号: 7274316
• 负责人: RICHARD P. PHIPPS
• 金额: $ 29.58万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-24 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7274316
• 关键词: 9-deoxy-delta-9-prostaglandin D2; Address; Adipocytes; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Atherosclerosis; Attenuated; Blood Platelets; Blood Vessels; CD40 Ligand; Cardiac; Cardiovascular Pathology; Cells; Clinical Trials; Coagulation Process; DNA Binding; Data; Deep Vein Thrombosis; Diabetes Mellitus; Dinoprostone; Disease; Disease Marker; Endothelial Cells; Exposure to; Fatty acid glycerol esters; Fibroblasts; Genes; Goals; Hematology; Human; Immunology; Indium; Inflammation; Inflammation Mediators; Inflammatory; Injury; Kinetics; Knockout Mice; Link; Location; Lymphocyte; Mediating; Mediator of activation protein; Modeling; Mus; Myocardial Infarction; PPAR gamma; Patients; Peroxisome Proliferator-Activated Receptors; Platelet Activation; Platelet aggregation; Play; Process; Production; Property; Prostaglandins; Proteins; Pulmonary Embolism; RXR; Research; Role; Scientist; Specificity; Staging; Stroke; Testing; Thinking; Thrombin; Thrombosis; Thromboxanes; Tissues; Vascular Diseases; cytokine; lipid biosynthesis; lipid metabolism; macrophage; multidisciplinary; novel; novel strategies; outcome forecast; pre-clinical; preclinical study; receptor; repaired; research study; rosiglitazone; small molecule; theories; transcription factor

DESCRIPTION (provided by applicant): As part of our long-term goal to develop new approaches to treat thrombotic diseases, we will investigate a novel mechanism that links platelets, inflammation and thrombosis. Platelets are crucial for the process of thrombosis, but are not widely considered as key elements in inflammation. An emerging view of platelets is that they contain and produce many immunomodulatory and proinflammatory mediators including CD40 ligand (CD40L), prostaglandins and cytokines. Platelets are not thought to possess transcription factors. However, our compelling preliminary data demonstrate that the transcription factor peroxisome proliferators activated receptor gamma (PPARgamma), believed only present in nucleated cells to regulate lipid metabolism, is highly expressed by platelets. Further, our experiments show that small molecule PPARgamma agonists, such as rosiglitazone and prostaglandin J2, inhibit platelet aggregation and ATP release. Remarkably, PPARgamma agonists inhibit the thrombin-induced production and release of key platelet mediators of inflammation including CD40L and thromboxanes. These findings are important because (1) thrombin is an extremely potent platelet activator, and (2) rosiglitazone and similar agents are already widely clinically employed in patients with diabetes. In addition to CD40L's known critical role in inflammation and atherosclerosis, it is now recognized as a primary platelet agonist important in thrombosis. CD40L is also a marker for disease activity and prognosis in cardiac and vascular diseases. Therefore, platelet PPARgamma is a new and previously unsuspected potential target to attenuate thrombosis, vascular injury and inflammation. We have developed the overall hypothesis that the transcription factor PPARgamma is expressed by platelets and modulates their ability to become activated and to produce mediators of inflammation that contribute to vascular injury. To provide a scientific framework to evaluate PPARgamma agonists as a possible therapy for thrombosis and inflammation, we will answer the following questions posed as our specific aims. Aim 1: What are the subcellular locations of platelet PPARgamma and what are the effects of PPARgamma agonists on platelet release of key proinflammatory mediators? Aim 2: How do PPARgamma agonists inhibit platelet activation and function? Aim 3: What is the significance of the PPARgamma protein that is expelled from platelets after activation? Completion of these studies will provide a scientific justification for clinical trials that employ existing PPARgamma agonists to attenuate atherothrombotic disease through modulation of platelet thrombotic and inflammatory functions.

描述（由申请人提供）：

项目成果

Providing ABO-identical platelets and cryoprecipitate to (almost) all patients: approach, logistics, and associated decreases in transfusion reaction and red blood cell alloimmunization incidence.

• DOI: 10.1111/j.1537-2995.2011.03329.x
• 发表时间: 2012-03
• 期刊: Transfusion
• 影响因子: 2.9
• 作者: Henrichs KF;Howk N;Masel DS;Thayer M;Refaai MA;Kirkley SA;Heal JM;Blumberg N
• 通讯作者: Blumberg N

Role of transfusion in the development of urinary tract-related bloodstream infection.

输血在尿路相关血流感染发展中的作用。

• DOI: 10.1001/archinternmed.2011.423
• 发表时间: 2011
• 期刊: Archives of internal medicine
• 作者: Rogers,MaryAM;Blumberg,Neil;Heal,JoannaM;Kuhn,Latoya;Greene,MTodd;Shuman,Emily;Chenoweth,CarolE;Chang,Robert;Saint,Sanjay
• 通讯作者: Saint,Sanjay

Platelet transfusions: trigger, dose, benefits, and risks.

• DOI: 10.3410/m2-5
• 发表时间: 2010-01-27
• 期刊: F1000 medicine reports
• 作者: Blumberg, Neil;Heal, Joanna M;Phillips, Gordon L
• 通讯作者: Phillips, Gordon L

Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer.

• DOI: 10.1001/archinte.168.21.2377
• 发表时间: 2008-11-24
• 期刊: ARCHIVES OF INTERNAL MEDICINE
• 作者: Khorana, Alok A.;Francis, Charles W.;Blumberg, Neil;Culakova, Eva;Refaai, Majed A.;Lyman, Gary H.
• 通讯作者: Lyman, Gary H.

Antigenic challenge in the etiology of autoimmune disease in women.

女性自身免疫性疾病病因学中的抗原挑战。

• DOI: 10.1016/j.jaut.2011.08.001
• 发表时间: 2012
• 期刊: Journal of autoimmunity
• 影响因子: 12.8
• 作者: Rogers,MaryAM;Levine,DeborahA;Blumberg,Neil;Fisher,GwenithG;Kabeto,Mohammed;Langa,KennethM
• 通讯作者: Langa,KennethM