Recent studies from our laboratory indicate that the close functional relationship between hematopoiesis and the vascular system first identified in early embryonic development extends into adult life. A single adult hematopoietic stem cell can differentiate into endothelial cells and blood cells, demonstrating the existence of adult cells with hemangioblast activity. Although bone marrow- derived hematopoietic stem cells (HSCs) and their progeny are thought to contribute to angiogenesis, relatively little is known about the identity of the progenitor cells involved and the mechanisms by which they contribute to blood vessel repair. We now hypothesize that the differentiation of HSCs into mature endothelial cells and the production of pro-angiogenic cytokines by HSCs and/or their progeny are critical factors regulating vascular endothelial homeostasis. To test this hypothesis, we propose to 1) determine the contribution of hematopoietic progenitors to the endothelial cell compartment during normal development; 2) evaluate the phenotype and functional activity of circulating pro-angiogenic hematopoietic cells; 3) determine the functional role of bone marrow derived endothelial cell progenitors during tissue regeneration. This research is significant as it is designed to identify novel cellular mechanisms responsible for vascular and hematopoietic system regeneration.

Public Health Relevance

The purpose of these studies is to enhance our knowledge of the close functional relationship between blood cell development and the vascular system. The results of this research have important implications for our understanding of disorders of the bone marrow and the vascular system. Ultimately this will lead to the identification of potential therapeutic targets for a number of diseases including leukemia, coronary artery disease and peripheral vascular disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL069133-05A2
Application #
7523714
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Thomas, John
Project Start
2001-09-30
Project End
2012-07-31
Budget Start
2008-08-15
Budget End
2009-07-31
Support Year
5
Fiscal Year
2008
Total Cost
$315,000
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Yao, Huilan; Goldman, Devorah C; Fan, Guang et al. (2015) The Corepressor Rcor1 Is Essential for Normal Myeloerythroid Lineage Differentiation. Stem Cells 33:3304-14
Yao, Huilan; Goldman, Devorah C; Nechiporuk, Tamilla et al. (2014) Corepressor Rcor1 is essential for murine erythropoiesis. Blood 123:3175-84
Cogle, Christopher R; Goldman, Devorah C; Madlambayan, Gerard J et al. (2014) Functional integration of acute myeloid leukemia into the vascular niche. Leukemia 28:1978-1987
Hakki, Morgan; Goldman, Devorah C; Streblow, Daniel N et al. (2014) HCMV infection of humanized mice after transplantation of G-CSF-mobilized peripheral blood stem cells from HCMV-seropositive donors. Biol Blood Marrow Transplant 20:132-5
Skinner, Amy M; Grompe, Markus; Kurre, Peter (2012) Intra-hematopoietic cell fusion as a source of somatic variation in the hematopoietic system. J Cell Sci 125:2837-43
Umashankar, Mahadevaiah; Petrucelli, Alex; Cicchini, Louis et al. (2011) A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection. PLoS Pathog 7:e1002444
Li, Bei; Bailey, Alexis S; Jiang, Shuguang et al. (2010) Endothelial cells mediate the regeneration of hematopoietic stem cells. Stem Cell Res 4:17-24
Smith, M Shane; Goldman, Devorah C; Bailey, Alexis S et al. (2010) Granulocyte-colony stimulating factor reactivates human cytomegalovirus in a latently infected humanized mouse model. Cell Host Microbe 8:284-91
Zhang, Qing-Shuo; Marquez-Loza, Laura; Eaton, Laura et al. (2010) Fancd2-/- mice have hematopoietic defects that can be partially corrected by resveratrol. Blood 116:5140-8
Kampa, Kerstin M; Acoba, Jared D; Chen, Dexi et al. (2009) Apoptosis-stimulating protein of p53 (ASPP2) heterozygous mice are tumor-prone and have attenuated cellular damage-response thresholds. Proc Natl Acad Sci U S A 106:4390-5

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