Hematopoietic cell transplantation (HCT) provides a potentially curative treatment for a wide variety of diseases. HCT, however, is complicated by high incidence of transplant-related mortality, graft failure and graft versus host disease (GvHD). The interaction of stromal derived factor-1 (SDF-1) with CXCR4 chemokine receptor plays an indispensable role in hematopoietic stem cell homing and engraftment. We hypothesize that blocking the SDF-1/CXCR4 interaction with a specific CXCR4 antagonist would selectively enhance donor cell reconstitution in allogeneic HCT. Plerixafor is a highly specific and reversible antagonist of CXCR4 and will be used in the current study. Our recent studies in a congeneic mouse transplant model demonstrated that post-transplant administration of plerixafor significantly improved animal survival and selectively enhanced donor cell engraftment. This selective enhancement of donor cell reconstitution results from combined effects of mobilization of residual recipient stem cells by plerixafor and selective survival advantage of donor stem cells. The objectives of this proposal are to perform pivotal translational studies to move our study into a phase I/II clinical trial at the end of this award and to further dissect the mechanisms of plerixafor and the regulation of CXCR4 signaling. We have 2 specific aims.
Our Aim 1 is to investigate the efficacy of plerixafor in enhancing donor cell engraftment in several allogeneic mouse transplant models that are directly relevant to clinical applications.
Our Aim 2 is to further dissect the mechanisms through which plerixafor enhances donor cell reconstitution and to understand the regulation of CXCR4 signaling. Successful accomplishment of these aims will have important implications in HCT and will benefit patients with HCT. Furthermore, our study will shed new lights into the role of CXCR4 in hematopoietic stem cell homing, mobilization and expansion, as well as the regulation of CXCR4 signaling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL103780-02
Application #
8328631
Study Section
Special Emphasis Panel (ZHL1-CSR-K (M4))
Program Officer
Welniak, Lisbeth A
Project Start
2011-09-05
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$131,571
Indirect Cost
$9,746
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
An, Ningfei; Kang, Yubin (2014) Thioredoxin and hematologic malignancies. Adv Cancer Res 122:245-79
An, Ningfei; Kraft, Andrew S; Kang, Yubin (2013) Abnormal hematopoietic phenotypes in Pim kinase triple knockout mice. J Hematol Oncol 6:12
An, Ningfei; Kang, Yubin (2013) Using quantitative real-time PCR to determine donor cell engraftment in a competitive murine bone marrow transplantation model. J Vis Exp :e50193
An, Ningfei; Janech, Michael G; Bland, Alison M et al. (2013) Proteomic analysis of murine bone marrow niche microenvironment identifies thioredoxin as a novel agent for radioprotection and for enhancing donor cell reconstitution. Exp Hematol 41:944-56
Coker, Woodrow J; Jeter, Ashley; Schade, Henning et al. (2013) Plasma cell disorders in HIV-infected patients: epidemiology and molecular mechanisms. Biomark Res 1:8
An, Ningfei; Lin, Ying-Wei; Mahajan, Sandeep et al. (2013) Pim1 serine/threonine kinase regulates the number and functions of murine hematopoietic stem cells. Stem Cells 31:1202-12