This proposal establishes a five year plan for Dr. Christopher R. Cogle to develop the skills and experience needed to become a successful clinician-scientist in the field of Hematology/Oncology. Currently, Dr. Cogle has completed one year of clinical fellowship and two years of mentored research under the direction of Dr. Edward W. Scott. In Dr. Scott's laboratory, Dr. Cogle has worked to define the role of human hematopoietic stem cells in remodeling blood vessels and other damaged tissues. Dr. Cogle's immediate goal is to broaden his research skills through a combination of a carefully structured didactic teaching program and completion of a research project in the laboratory of his mentor. Dr. Cogle's long-term goal is to become an independent investigator capable of combining the discipline of stem cell biology with issues in clinical hematology, oncology and bone marrow transplantation. Dr. Cogle's research project is based on the hypothesis that the human hematopoietic stem cell (HSC) can act as a functional hemangioblast, contributing to both hematopoiesis and reparative vasculogenesis. The hypothesis is based on observations in the Scott laboratory where a novel murine model of diabetic retinopathy clearly showed that adult murine HSC act as functional hemangioblasts. In mice receiving single cell HSC transplant and secondary transplants, retinal injury resulted in multiple neovascular tufts derived from donor HSCs. During Dr. Cogle's mentored research fellowship in the Scott laboratory, he established a human HSC xenograft model in NOD/scid mice to test whether human HSC also provide functional hemangioblast activity. Functional transdifferentiation will be defined by confocal microscopy, serial sectioning, immunohistochemistry with multiple markers, and karyotyping. Additionally, vascular tissue samples from female patients having received bone marrow transplantation from male donors will be analyzed for presence of transgender endothelial cells. Ultimately, these results point toward the clinical application of targeting bone marrow-derived endothelial progenitor cells (EPCs) homing to sites of vascular remodeling. Dr. Scott's laboratory provides an excellent environment for Dr. Cogle to carry out this proposal. In this rich and supportive environment, Dr. Cogle will gain the experience necessary to contribute to the understanding of reparative vasculogenesis and stem cell transdifferentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK067359-03
Application #
7235593
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Bishop, Terry Rogers
Project Start
2005-06-01
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$123,390
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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
Kirabo, Annet; Park, Sung O; Wamsley, Heather L et al. (2012) The small molecule inhibitor G6 significantly reduces bone marrow fibrosis and the mutant burden in a mouse model of Jak2-mediated myelofibrosis. Am J Pathol 181:858-65
Kirabo, Annet; Embury, Jennifer; Kiss, RĂ³bert et al. (2011) The stilbenoid tyrosine kinase inhibitor, G6, suppresses Jak2-V617F-mediated human pathological cell growth in vitro and in vivo. J Biol Chem 286:4280-91
Kirabo, Annet; Park, Sung O; Majumder, Anurima et al. (2011) The Jak2 inhibitor, G6, alleviates Jak2-V617F-mediated myeloproliferative neoplasia by providing significant therapeutic efficacy to the bone marrow. Neoplasia 13:1058-68
Madlambayan, Gerard J; Meacham, Amy M; Hosaka, Koji et al. (2010) Leukemia regression by vascular disruption and antiangiogenic therapy. Blood 116:1539-47
Cogle, Christopher R; Imanirad, Iman; Wiggins, Laura E et al. (2010) Hypomethylating agent induction therapy followed by hematopoietic cell transplantation is feasible in patients with myelodysplastic syndromes. Clin Adv Hematol Oncol 8:40-6
Ucar, Deniz; Cogle, Christopher R; Zucali, James R et al. (2009) Aldehyde dehydrogenase activity as a functional marker for lung cancer. Chem Biol Interact 178:48-55
Madlambayan, Gerard J; Butler, Jason M; Hosaka, Koji et al. (2009) Bone marrow stem and progenitor cell contribution to neovasculogenesis is dependent on model system with SDF-1 as a permissive trigger. Blood 114:4310-9
Cogle, Christopher R; Theise, Neil D; Fu, Dongtao et al. (2007) Bone marrow contributes to epithelial cancers in mice and humans as developmental mimicry. Stem Cells 25:1881-7