The major objective of this proposal is the development of the candidate's academic career in laboratory research of immune pathology that develops after bone marrow transplantation. For 2.5 years, the candidate was funded by a Paul Calebrisi K12 Grant (Dr. Bruce Chabner, PI) at the Harvard Cancer Center as a post- doctoral in Dr. Jerome Ritz'laboratory at Dana-Farber Cancer Institute. The candidate now proposes a mentorship plan at the University of North Carolina (UNC), Chapel Hill where she began a tenure-track faculty position on June 1st, 2009. The UNC K08 mentorship program will be headed by Albert Baldwin, Ph.D., who will serve as the candidate's primary mentor. Dr. Baldwin is a leading expert in NFkB signaling with a long track record of successfully mentoring young investigators. He has developed a comprehensive mentorship plan for the candidate primarily focused on developing her knowledge and experimental expertise in TNF family member receptor signaling. The candidate's co-mentor will be Dr. Serody who is an endowed Professor of Medicine, Microbiology and Immunology and co-leader of the Immunology Section in the Lineberger Cancer Center. Dr. Serody is recognized as a leader in the field of Graft versus Host Disease (GVHD) having led several NIH-funded laboratory studies focused on the role of chemokine receptors and immune regulatory cells in GVHD. A comprehensive clinical data base developed by one of the candidate's key collaborators, Dr. Thomas Shea, in conjunction with an IRB tissue procurement protocol at UNC will allow Dr. Sarantopoulos to collect and characterize samples from patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT). In addition, Dr. Jerome Ritz from Dana-Farber Cancer Center, Dr. Nelson Chao from Duke University and Dr. Stephanie Lee from Fred Hutchinson Cancer Center will collaborate and supply the candidate with fresh and cryopreserved HSCT patient samples. Finally, Dr. Sarantopoulos has assembled a local UNC expert scientific advisory committee comprised of Dr. Stephen Clarke and Dr. Barbara Vilen in the, Department Microbiology &Immunology at UNC, both experts in B cell pathobiology. Her mentors and expert advisory committee will enable the candidate to combine what she has previously learned and accomplished with detailed, specific apprenticeship training in TNF family member receptor signaling. Research will focus on studies of significant immune pathology that develops in patients after treatment for cancer with allogeneic hematopoietic stem cell transplantation (HSCT). The long-term goal of this research project is to understand the role of B cell Activating Factor of the TNF family (BAFF) and its associated signaling pathways. The proposed experiments will allow for future development of novel targeted therapeutic agents for chronic GVHD and improved overall survival of cancer patients. The mentorship, didactics, and research proposal along with the academic and research infrastructure provided by UNC and the Lineberger Comprehensive Cancer Center will ensure the candidate's successful transition to an NIH-funded independent investigator.
NARRATIVE Allogeneic hematopoietic cell transplantation (HCST) is the only known curative option for many of the approximately 40 per 100,000 Americans afflicted with life-threatening blood-borne cancers. After HCST, chronic graft versus host disease (cGVHD) develops in 30-70% of patients carrying an impact on survival that has not improved significantly over the last 30 years. The current research will advance knowledge about immunopathologic mechanisms in human cGVHD. Our findings have implications for treatment of neoplastic, autoimmune and infectious diseases.
|Du, Jing; Paz, Katelyn; Flynn, Ryan et al. (2017) Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-? production. Blood 129:2570-2580|
|Du, Jing; Paz, Katelyn; Thangavelu, Govindarajan et al. (2017) Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells. Blood 129:3121-3125|
|Flynn, Ryan; Paz, Katelyn; Du, Jing et al. (2016) Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood 127:2144-54|
|Sarantopoulos, Stefanie; Blazar, Bruce R; Cutler, Corey et al. (2015) B cells in chronic graft-versus-host disease. Biol Blood Marrow Transplant 21:16-23|
|Sarantopoulos, Stefanie; Ritz, Jerome (2015) Aberrant B-cell homeostasis in chronic GVHD. Blood 125:1703-7|
|Allen, Jessica L; Tata, Prasanthi V; Fore, Matthew S et al. (2014) Increased BCR responsiveness in B cells from patients with chronic GVHD. Blood 123:2108-15|
|Jacobson, Caron A; Sun, Lixian; Kim, Haesook T et al. (2014) Post-transplantation B cell activating factor and B cell recovery before onset of chronic graft-versus-host disease. Biol Blood Marrow Transplant 20:668-75|
|Sarantopoulos, Stefanie; Su, Maureen A (2013) BAFF-ling autoantibodies. J Clin Invest 123:5006-8|
|Cutler, Corey; Kim, Haesook T; Bindra, Bhavjot et al. (2013) Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial. Blood 122:1510-7|
|Allen, Jessica L; Fore, Matthew S; Wooten, Jenna et al. (2012) B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways. Blood 120:2529-36|
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