Microparticles as Messengers of Communication Between Blood and Vascular Cells

Summary

Principal Investigator: Richard P Phipps
Abstract: This RC1 grant application is responsive to Challenge Area "04-Clinical Research" and specifically to the NHLBI Challenge Topic 04-HL-103: "Assess the role of leukocyte interaction with platelets, erythrocytes, and endothelium in the pathogenesis of heart, lung, and blood diseases." A significant knowledge gap is how the platelet communicates with other blood and vascular cells. Knowledge of this process could lead to improved disease management and biomarker development. The small anucleate platelet plays a seminal role not only in hemostasis, but also in diabetes and cardiovascular disease which affect millions of Americans. Further interest in the platelet is fueled by the fact that millions of units of platelets are transfused each year, sometimes with deleterious consequences. Platelets are now also recognized as key inducers of inflammation. Our laboratory discovered that platelets abundantly express the transcription factor peroxisome proliferator activated receptor-gamma (PPAR?) and that PPAR? ligands dampen platelet activation. Ligand activated PPAR? is a previously unrecognized target that attenuates unwanted platelet activation in patients with type 2 diabetes or cardiovascular disease. PPAR? is viewed as an anti-inflammatory transcription factor, which also functions via non-nuclear mechanisms. Our team recently discovered that PPAR? is released from platelets in microparticles (MPs). MPs are submicron membrane vesicles that contain bioactive proteins and mediators. PPAR? containing MPs are taken up by and dampen macrophage function. We also discovered that type-2 diabetics produce MPs that have abnormally low levels of PPAR? and are likely to stimulate inflammation rather than inhibit it. We propose the overall challenge and hypothesis that PPAR? in MPs influences other cells by a transcellular mechanism. To complete this challenge in 2 years we assembled an outstanding multidisciplinary team to complete 2 aims. Aim 1: Investigate platelet MPs containing PPAR? and determine their ability to influence key white blood cell and vascular cell functions. Purified platelets from normal and type-2 diabetics will be used to generate MPs in vitro under controlled conditions. We will study their ability to be taken up and influence blood monocytes/macrophages and blood vessel endothelial cells. Thus, we will identify a new form of cell-cell communication. Genetic systems and a preclinical mouse model will be used to study the role of PPAR?-containing platelet MPs in health and disease. Aim 2: Discovery and characterization of MPs containing PPAR? in the blood of normal humans and those with type-2 diabetes. We will determine the cellular sources in blood of PPAR? containing MPs. While some MPs will be of platelet origin (Aim 1), others could come from white blood cells or vascular endothelial cells. The patterns of MPs and cell of origin could be used as a biomarker of disease and response to therapy. This new information could be used to develop an "artificial MP" to deliver PPAR? to cells of choice leading to a new therapeutic paradigm in diabetes and cardiovascular disease. Type-2 diabetes and its consequences, particularly cardiovascular disease, affect millions of Americans. This project will study how small blood cells called platelets, which prevent bleeding, communicate with other blood and vascular cells in healthy and type-2 diabetic individuals. Platelets, when stimulated, release small parts of themselves that contain instructions that other cells take up and which then change their behavior. Understanding this new way of cell to cell communication will lead to new methods and biomarkers to detect disease and to new ways of delivering therapy to reduce the consequences of diabetes and other diseases. PUBLIC HEALTH RELEVANCE: Type-2 diabetes and its consequences, particularly cardiovascular disease, affect millions of Americans. This project will study how small blood cells called platelets, which prevent bleeding, communicate with other blood and vascular cells in healthy and type-2 diabetic individuals. Platelets, when stimulated, release small parts of themselves that contain instructions that other cells take up and which then change their behavior. Understanding this new way of cell to cell communication will lead to new methods and biomarkers to detect disease and to new ways of delivering therapy to reduce the consequences of diabetes and other diseases.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Isoprostane and isofuran lipid mediators accumulate in stored red blood cells and influence platelet function in vitro
    Sherry L Spinelli
    Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
    Transfusion 54:1569-79. 2014
  2. pmc Transfusion immunomodulation--the case for leukoreduced and (perhaps) washed transfusions
    Katie L Lannan
    Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
    Blood Cells Mol Dis 50:61-8. 2013
  3. pmc Alterations of platelet function and clot formation kinetics after in vitro exposure to anti-A and -B
    Majed A Refaai
    Department of Pathology and Laboratory Medicine, The James P Wilmot Cancer Center, University of Rochester, Rochester, New York 14642, USA
    Transfusion 53:382-93. 2013
  4. ncbi Pioglitazone inhibits platelet function and potentiates the effects of aspirin: a prospective observation study
    John Mongan
    University of Rochester Medical Center, Department of Medicine Hematology Oncology, Rochester, NY 14642, USA
    Thromb Res 129:760-4. 2012
  5. pmc Washing red blood cells and platelets transfused in cardiac surgery reduces postoperative inflammation and number of transfusions: results of a prospective, randomized, controlled clinical trial
    Jill M Cholette
    Department of Pediatrics, University of Rochester, Rochester, NY, USA
    Pediatr Crit Care Med 13:290-9. 2012
  6. pmc Providing ABO-identical platelets and cryoprecipitate to (almost) all patients: approach, logistics, and associated decreases in transfusion reaction and red blood cell alloimmunization incidence
    Kelly F Henrichs
    Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    Transfusion 52:635-40. 2012
  7. pmc Antigenic challenge in the etiology of autoimmune disease in women
    Mary A M Rogers
    Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109 0429, USA
    J Autoimmun 38:J97-J102. 2012
  8. pmc New frontiers in transfusion biology: identification and significance of mediators of morbidity and mortality in stored red blood cells
    Katie Grimshaw
    Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
    Transfusion 51:874-80. 2011
  9. pmc An association of ABO non-identical platelet and cryoprecipitate transfusions with altered red cell transfusion needs in surgical patients
    Majed A Refaai
    Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, NY, USA
    Vox Sang 101:55-60. 2011
  10. pmc The Feverfew plant-derived compound, parthenolide enhances platelet production and attenuates platelet activation through NF-κB inhibition
    Julie Sahler
    Department of Microbiology and Immunology, University of Rochester, Rochester, NY, USA
    Thromb Res 127:426-34. 2011

Scientific Experts

  • Neil Blumberg
  • Mary Am Rogers
  • Jill M Cholette
  • Majed A Refaai
  • Sherry L Spinelli
  • Richard P Phipps
  • Julie Sahler
  • Katie L Lannan
  • Kelly F Henrichs
  • Charles W Francis
  • Sanjay B Maggirwar
  • John Mongan
  • Stephen J Pollock
  • Ann E Casey
  • Katie Grimshaw
  • Donna C Davidson
  • Ginger A Milne
  • Amanda Croasdell
  • Timothy M Curran
  • Debra S Masel
  • Joanna M Heal
  • Scott A Kirkley
  • Hanna Z Mieszczanska
  • Nedda Howk
  • Brian H Smith
  • Susan P Messing
  • Mark Thayer
  • Craig N Morrell
  • Michael P Hirschman
  • Giovanni Schifitto
  • Jamie J Bernard
  • Srinivasa D Narasipura
  • David H McMillan
  • Jacqueline M Gertz
  • Mark B Taubman
  • Michael R King
  • Nipa A Mody

Detail Information

Publications18

  1. pmc Isoprostane and isofuran lipid mediators accumulate in stored red blood cells and influence platelet function in vitro
    Sherry L Spinelli
    Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
    Transfusion 54:1569-79. 2014
    ..This study investigated RBC-derived F2 -IsoPs and IsoFs during storage and their influence on human platelets (PLTs)...
  2. pmc Transfusion immunomodulation--the case for leukoreduced and (perhaps) washed transfusions
    Katie L Lannan
    Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
    Blood Cells Mol Dis 50:61-8. 2013
    ..The present review will focus on two approaches, leukoreduction and saline washing, as means to reduce adverse transfusion outcomes...
  3. pmc Alterations of platelet function and clot formation kinetics after in vitro exposure to anti-A and -B
    Majed A Refaai
    Department of Pathology and Laboratory Medicine, The James P Wilmot Cancer Center, University of Rochester, Rochester, New York 14642, USA
    Transfusion 53:382-93. 2013
    ..We present here in vitro modeling data on the functional effects of exposure of PLTs to ABO antibodies...
  4. ncbi Pioglitazone inhibits platelet function and potentiates the effects of aspirin: a prospective observation study
    John Mongan
    University of Rochester Medical Center, Department of Medicine Hematology Oncology, Rochester, NY 14642, USA
    Thromb Res 129:760-4. 2012
    ..Thiazolidinediones (TZDs) are agonists of PPARγ and exert beneficial metabolic effects in patients with diabetes. They may also affect platelet function...
  5. pmc Washing red blood cells and platelets transfused in cardiac surgery reduces postoperative inflammation and number of transfusions: results of a prospective, randomized, controlled clinical trial
    Jill M Cholette
    Department of Pediatrics, University of Rochester, Rochester, NY, USA
    Pediatr Crit Care Med 13:290-9. 2012
    ..We hypothesize that washing red blood cells and platelets transfused to these patients will reduce postoperative transfusion-related immune modulation and inflammation...
  6. pmc Providing ABO-identical platelets and cryoprecipitate to (almost) all patients: approach, logistics, and associated decreases in transfusion reaction and red blood cell alloimmunization incidence
    Kelly F Henrichs
    Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    Transfusion 52:635-40. 2012
    ..In April 2005, we implemented a policy of transfusing only ABO-identical components whenever feasible, regardless of outdating or logistic considerations...
  7. pmc Antigenic challenge in the etiology of autoimmune disease in women
    Mary A M Rogers
    Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109 0429, USA
    J Autoimmun 38:J97-J102. 2012
    ..Antigenic challenges, such as infection and allogeneic blood transfusion, are significant risk factors for the development of autoimmune disease in older women...
  8. pmc New frontiers in transfusion biology: identification and significance of mediators of morbidity and mortality in stored red blood cells
    Katie Grimshaw
    Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
    Transfusion 51:874-80. 2011
    ..These mediators likely play a direct role in the inflammatory and prothrombotic properties of RBC transfusions. Methods such as leukoreduction, washing of RBCs, and rejuvenation may improve the quality of RBC transfusions...
  9. pmc An association of ABO non-identical platelet and cryoprecipitate transfusions with altered red cell transfusion needs in surgical patients
    Majed A Refaai
    Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, NY, USA
    Vox Sang 101:55-60. 2011
    ..Transfusion of ABO non-identical plasma, platelets and cryoprecipitate is routine practice even though adverse effects can occur...
  10. pmc The Feverfew plant-derived compound, parthenolide enhances platelet production and attenuates platelet activation through NF-κB inhibition
    Julie Sahler
    Department of Microbiology and Immunology, University of Rochester, Rochester, NY, USA
    Thromb Res 127:426-34. 2011
    ..We investigated the effect of the feverfew plant-derived compound, parthenolide on platelet production and platelet activation because of its well-studied ability to induce apoptosis or differentiation in some types of cancer...
  11. pmc Antiplatelet activity of valproic acid contributes to decreased soluble CD40 ligand production in HIV type 1-infected individuals
    Donna C Davidson
    Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    J Immunol 186:584-91. 2011
    ....
  12. pmc Platelet transfusions: impact on hemostasis, thrombosis, inflammation and clinical outcomes
    Majed A Refaai
    Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
    Thromb Res 127:287-91. 2011
    ..In this review, we will briefly highlight the importance of platelet transfusion, its role in inflammatory and thrombotic transfusion reactions, and visit the most recent findings on sCD40L...
  13. ncbi Nuclear emancipation: a platelet tour de force
    Sherry L Spinelli
    Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Sci Signal 3:pe37. 2010
    ..Our appreciation of the role of transcription factors in mammalian platelet biology is nascent but holds great promise for both understanding platelet function and translation into clinical uses...
  14. pmc An association between decreased cardiopulmonary complications (transfusion-related acute lung injury and transfusion-associated circulatory overload) and implementation of universal leukoreduction of blood transfusions
    Neil Blumberg
    Transfusion Medicine Unit, and the Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA
    Transfusion 50:2738-44. 2010
    ..Cardiopulmonary adverse events after transfusion include transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO), which are potentially lethal and incompletely understood...
  15. pmc Platelets and megakaryocytes contain functional nuclear factor-kappaB
    Sherry L Spinelli
    Department of Environmental Medicine, Box 850, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642, USA
    Arterioscler Thromb Vasc Biol 30:591-8. 2010
    ..We discovered that human megakaryocytes and platelets express the majority of NF-kappaB family members, including the regulatory inhibitor-kappaB (I-kappaB) and I-kappa kinase (IKK) molecules...