Autoimmune mechanisms are known to play a role in the thrombocytopenia observed in individuals infected with the human immunodeficiency virus (HIV) who suffer from the Acquired Immune Deficiency Syndrome (AIDS). However, immunologic mechanisms alone are unlikely to account for all aspects of the pathogenesis of thrombocytopenia seen in AIDS. Among these other mechanisms are possible direct effects of the HIV, or its associated proteins, on the development of megakaryopoietic progenitors in the bone marrow, or the ability of these cells to carry out thrombopoiesis, the process of platelet production. It is also possible that these effects may be brought about indirectly by effects of the virus, or viral proteins, on marrow stromal and accessory cells supportive of megakaryocytopoiesis. To investigate these issues, The applicants propose the following four specific aims: I. Determine the effect of HIV infection on megakaryopoiesis and platelet formation. They will infect human megakaryocytic cells at various stages of development with HIV-1 and HIV-2 viruses and examine the ability of these cells to differentiate into mature megakaryocytes and form platelets. If these processes are impaired, they will determine the mechanism(s) involved. II. Characterize the chemokine receptors on megakaryocytes and the influence of their corresponding ligands on megakaryopoiesis. They will characterize the chemokine receptors displayed on uninfected and infected megakaryocytes, and study the influence of these receptor-ligand pairs on the developmental biology of these cells. These studies will shed light on the function of these chemokines during megakaryocytopoiesis and thrombopoiesis. III. Investigate the role of HIV proteins and HIV-induced cytokines on thrombocytopenia. They will evaluate the influence of viral proteins and inflammatory cytokines elaborated during infection by accessory cells on the developmental biology of megakaryopoietic precursors and mature cells. IV. Develop strategies for preventing HIV-induced thrombocytopenia. Inhibitory mutants of chemokines have already been developed and shown to prevent HIV infection. Based on findings in the first 3 specific aims, they plan to test blocking chemokines and monoclonal antibodies, and blocking of various cytokines on megakaryopoiesis both ex vivo and in NOD/SCID (non obese diabetic/severe combined immunodeficiency) mice/human hematopoietic chimeras. In toto, the studies proposed in this grant will increase the knowledge about pathogenesis of AIDS associated thrombocytopenia and may lead to development of new strategies for its treatment of prevention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061796-02
Application #
6056567
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S1))
Project Start
1998-09-30
Project End
2003-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ratajczak, Mariusz Z; Borkowska, Sylwia; Ratajczak, Janina (2013) An emerging link in stem cell mobilization between activation of the complement cascade and the chemotactic gradient of sphingosine-1-phosphate. Prostaglandins Other Lipid Mediat 104-105:122-9
Ratajczak, Mariusz Z; Kim, ChiHwa; Ratajczak, Janina et al. (2013) Innate immunity as orchestrator of bone marrow homing for hematopoietic stem/progenitor cells. Adv Exp Med Biol 735:219-32
Janowska-Wieczorek, Anna; Marquez-Curtis, Leah A; Wysoczynski, Marcin et al. (2006) Enhancing effect of platelet-derived microvesicles on the invasive potential of breast cancer cells. Transfusion 46:1199-209
Janowska-Wieczorek, Anna; Wysoczynski, Marcin; Kijowski, Jacek et al. (2005) Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 113:752-60
Honczarenko, Marek; Ratajczak, Mariusz Z; Nicholson-Weller, Anne et al. (2005) Complement C3a enhances CXCL12 (SDF-1)-mediated chemotaxis of bone marrow hematopoietic cells independently of C3a receptor. J Immunol 175:3698-706
Ratajczak, Mariusz Z (2005) Cancer stem cells--normal stem cells ""Jedi"" that went over to the ""dark side"". Folia Histochem Cytobiol 43:175-81
Wysoczynski, Marcin; Reca, Ryan; Ratajczak, Janina et al. (2005) Incorporation of CXCR4 into membrane lipid rafts primes homing-related responses of hematopoietic stem/progenitor cells to an SDF-1 gradient. Blood 105:40-8
Kucia, Magda; Ratajczak, Janina; Ratajczak, Mariusz Z (2005) Bone marrow as a source of circulating CXCR4+ tissue-committed stem cells. Biol Cell 97:133-46
Kucia, Magda; Ratajczak, Janina; Ratajczak, Mariusz Z (2005) Are bone marrow stem cells plastic or heterogenous--that is the question. Exp Hematol 33:613-23
Ratajczak, Janina; Reca, Ryan; Kucia, Magda et al. (2004) Mobilization studies in mice deficient in either C3 or C3a receptor (C3aR) reveal a novel role for complement in retention of hematopoietic stem/progenitor cells in bone marrow. Blood 103:2071-8

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