The hematological disorders of mice lacking heme oxygenase 1 (HO-1) include hypoferremia, tissue accumulation of iron, and anemia by 20 weeks of age. In a rare human case, HO-1 deficiency was accompanied by anemia, growth retardation, leukocytosis, thrombocytosis, coagulation abnormality, and death at an early age. These disorders in mice and human suggest an important role of HO-1 in hematopoiesis, and that a thorough investigation into the role of HO- 1 is warrented. Our preliminary data indicate that there is a severe hematopoietic defect intrinsic to HSC in HO-1 deficient mice, associated with increased frequency of HSCs and progenitors in BM under steady-state condition and accelerated cell division of primitive cells after adoptive transfer, suggesting a rather unique and complexed molecular mechanism. We hypothesize that 1) HO-1 is essential for normal HSCfunctions and hematopoiesis. In the absence of HO-1, HSCs will be defective and hematopoiesis will be severely impaired in producing mature blood cell of all lineages, especially under hematopoietic stress; 2) this protective role of HO-1 is achieved by regulating the complex balance between quiescence, self-renewal, and differentiation of HSCs, and that loss of HO-1 leads to over-recruitment of HSCs from G0 into d, and drives the HSCs toward differentiation over self-renewal, leading to ultimate depletion of the HSCpool. To test this hypothesis, I have proposed three specific aims: 1) Characterize the hematopoietic defect in HO-1 deficient mice, and evaluate its severity; 2) Investigate the essential role of HO-1 in the function of HSCs and progenitors, evaluate the affect of HO-1 deficiency on lineage development; 3) Analyze the quiescence, cell cycle status, and cell cycle modulator levels of HSCs under normal and myeloablation conditions. Understanding the HO-1 deficiency associated hematopoetic defect may reveal a unique pathway for regulating the balance between HSC self-renewal and differentiation and hematopoiesis, and eventually lead to more effective therapies for certain types of hematological diseases and more efficient protocols for bone marrow transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK071716-04
Application #
7478348
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Bishop, Terry Rogers
Project Start
2005-09-15
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
4
Fiscal Year
2008
Total Cost
$132,705
Indirect Cost
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305