Thrombocytopenia is one of the life threatening hematologic disorders that may occur as a result of autoimmune process or during the asymptomatic and clinical stage of HIV-1 infection. It is hypothesized that disruption of chemokine network, and adhesive interactions between megakaryocytes (MKs) and bone marrow endothelium (BMEC) as it may occur during HIV infection, plays a seminal role in the failure of MK transmigration and platelet release. The exact mechanism and site of platelet formation is not well defined. Studies have shown that transmigration of MK through BMEC, may be critical for platelet formation. The investigators have discovered that mature polypoid MKs express the chemokine receptor (HIV co-receptor): CXCR4. Stromal Derived Factor 1 (SDF1) which is the ligand for the CXCR4, promotes transmigration of MKs through BMEC monolayers. They have also identified a novel endothelial cell derived factor (ECDF1) that selectively induce migration of MKs through BMEC. Transendothelial migration of MKs in response to SDF1 or ECDF1 enhances formation of functional platelets. Interaction of migration MK with adhesion molecules expressed on MBEC such as E-selectin and PECAM is critical for MK migration and optimal platelet formation. They have also discovered that HIV can inject MKs through CXCR receptor, interfering with transendothelial migration of Mks, and platelet release. In this proposal they plan to 1) Define the mechanism whereby SDF1 and ECDF1 modulate adhesion molecule adhesion molecule expression of MK and BMEC cells. 2) Characterize cellular signaling pathways such as apoptotic pathways that may be induced by transmigration of Mks. 3) Take advantage of the availability of MK and BMEC derived from E-selectin knockout mice to study the role of these factors in regulation of CXCR expression. Both MKs and BMEC express CD4 and CXCR4, and are therefore susceptible to HIV infection. Therefore, it is planned to define the mechanism whereby HIV infection of either Mks and BMEC may influence chemokine receptor, and adhesion molecule expression resulting in dysfunction or platelet formation. Whether HIV-1 gp120 or other factors including megakaryopoietins that interact with CXCR4 may also influence platelet formation will also be explored. They plan to over-express CXCR4 and SDF1 within the milieu of marrow microenvironment by adenoviral vectors to explore the possibility of augmenting platelet production. This project should lead to the definition of the role of chemokines and adhesion molecules expressed by BMEC that regulate platelet production. Identification of chemokine receptors that may regulate platelet production may elucidate pathogenesis of thrombocytopenia in HIV or other thrombocytopenic states and suggest potential pharmacological interventions. Modulation of chemokine receptors expression by adenoviral vectors overexpressing SDF1, ECDF1 or their receptors may allow for developing therapies to ameliorate thrombocytopenia in vivo.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061849-02
Application #
6056573
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
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Rabbany, Sina Y; James, Daylon; Rafii, Shahin (2010) New dimensions in vascular engineering: opportunities for cancer biology. Tissue Eng Part A 16:2157-9
Rafii, Shahin; Nolan, Daniel (2010) Cholesterol activates vascular niche and hematopoiesis. Blood 115:3857-8
Yamamoto, Masaya; James, Daylon; Li, Hui et al. (2010) Generation of stable co-cultures of vascular cells in a honeycomb alginate scaffold. Tissue Eng Part A 16:299-308
Butler, Jason M; Kobayashi, Hideki; Rafii, Shahin (2010) Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer 10:138-46
James, Daylon; Nam, Hyung-song; Seandel, Marco et al. (2010) Expansion and maintenance of human embryonic stem cell-derived endothelial cells by TGFbeta inhibition is Id1 dependent. Nat Biotechnol 28:161-6
Hooper, Andrea T; Shmelkov, Sergey V; Gupta, Sunny et al. (2009) Angiomodulin is a specific marker of vasculature and regulates vascular endothelial growth factor-A-dependent neoangiogenesis. Circ Res 105:201-8
Kopp, Hans-Georg; Hooper, Andrea T; Avecilla, Scott T et al. (2009) Functional heterogeneity of the bone marrow vascular niche. Ann N Y Acad Sci 1176:47-54
Hooper, Andrea T; Butler, Jason M; Nolan, Daniel J et al. (2009) Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell 4:263-74
Rafii, Shahin; Lyden, David (2008) Cancer. A few to flip the angiogenic switch. Science 319:163-4
Seandel, Marco; Butler, Jason; Lyden, David et al. (2008) A catalytic role for proangiogenic marrow-derived cells in tumor neovascularization. Cancer Cell 13:181-3

Showing the most recent 10 out of 51 publications