Abstract

? Hematopoietic stem cells (HSCs) are the only cells within the bone marrow that possess the ability to both differentiate to all blood lineages and to self-renew for life. These two properties allow for the proper maintenance of hematopoietic homeostasis, but genetic abnormalities within HSCs can lead to profound negative consequences such as immunodeficiency, anemia, or leukemia. Because the replacement of genetically abnormal HSCs with normal HSCs can correct many of these diseases, it is of critical importance to understand how best to achieve such an exchange while minimizing risk to the patient. One of the most important parameters for the success of bone marrow transplantations is the availability of sufficient numbers of appropriate bone marrow microenvironments for donor HSCs to engraft. The research proposal outlined below describes a series of both classical and technologically novel approaches designed to better understand the functional interactions of HSCs with the highly specific bone marrow microenvironments in which they reside and the potential for therapeutic intervention by capitalizing upon these dynamic interactions. It is anticipated that significant contributions to this field will allow me to transition to an independent faculty position within the next 3 years. ? Specific Aims: ? Aim 1: To characterize the kinetics, magnitude, and therapeutic potential of HSC niche emptying and refilling under steady state conditions. ? Aim 2: To isolate and characterize HSC-supportive niche cells. ? Aim 3: To localize and visualize HSC homing and engraftment in vivo. Relevance: The hematopoietic stem cell is a remarkable cell type that exists within the bone marrow and is responsible for the production of all red and white blood cells for life. In order for them to function appropriately, they must reside within specific areas, or niches, within the bone marrow. The goal of this proposal is to better characterize the properties of these niches and to determine how best to utilize these niches for bone marrow transplantation. ? ?

  Funding Agency

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 #
7K01DK078318-02
Application #
7429717
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Bishop, Terry Rogers
Project Start
2007-09-01
Project End
2012-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
2
Fiscal Year
2008
Total Cost
$132,057
Indirect Cost

  Institution

Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Becker, Amy M; Walcheck, Bruce; Bhattacharya, Deepta (2015) ADAM17 limits the expression of CSF1R on murine hematopoietic progenitors. Exp Hematol 43:44-52.e1-3
Becker, Amy M; Callahan, Derrick J; Richner, Justin M et al. (2015) GPR18 Controls Reconstitution of Mouse Small Intestine Intraepithelial Lymphocytes following Bone Marrow Transplantation. PLoS One 10:e0133854
Satpathy, Ansuman T; Briseño, Carlos G; Cai, Xiongwei et al. (2014) Runx1 and Cbf? regulate the development of Flt3+ dendritic cell progenitors and restrict myeloproliferative disorder. Blood 123:2968-77
Sandoval, Gabriel J; Graham, Daniel B; Bhattacharya, Deepta et al. (2013) Cutting edge: cell-autonomous control of IL-7 response revealed in a novel stage of precursor B cells. J Immunol 190:2485-9
Becker, Amy M; Michael, Drew G; Satpathy, Ansuman T et al. (2012) IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid mouse progenitors. Blood 119:2003-12
Purtha, Whitney E; Swiecki, Melissa; Colonna, Marco et al. (2012) Spontaneous mutation of the Dock2 gene in Irf5-/- mice complicates interpretation of type I interferon production and antibody responses. Proc Natl Acad Sci U S A 109:E898-904
Fathman, John W; Bhattacharya, Deepta; Inlay, Matthew A et al. (2011) Identification of the earliest natural killer cell-committed progenitor in murine bone marrow. Blood 118:5439-47
Sahoo, Debashis; Seita, Jun; Bhattacharya, Deepta et al. (2010) MiDReG: a method of mining developmentally regulated genes using Boolean implications. Proc Natl Acad Sci U S A 107:5732-7
Beerman, Isabel; Bhattacharya, Deepta; Zandi, Sasan et al. (2010) Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci U S A 107:5465-70
Inlay, Matthew A; Bhattacharya, Deepta; Sahoo, Debashis et al. (2009) Ly6d marks the earliest stage of B-cell specification and identifies the branchpoint between B-cell and T-cell development. Genes Dev 23:2376-81

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