Allogeneic blood and marrow transplantation (alloBMT) is used as a curative therapy for blood cancers with more than 8,000 transplants performed yearly in the United States. Graft-versus-host disease (GVHD) affects the majority of transplant recipients and its chronic form (cGVHD) is the major cause of late transplant morbidity, mortality, and overall therapeutic alloBMT failure. A growing body of data identifies the immediate post-transplant period as critical for successful cGVHD prevention and overall alloBMT success. I have demonstrated that Notch is active at early and late stages of cGVHD, but the earliest T cell imprinting by Notch is most critical to trigger severe cGVHD and associated global immune dysfunction. I hypothesize that Notch promotes pathogenic alloresponses by regulating the earliest transcriptional programs of alloreactive T and B cells, and these genetic signatures include potential targets for mechanism-based cGVHD prevention and treatment without negative impact on desirable immune effects of alloBMT. To test this hypothesis, I have optimized cGVHD models to allow tracking of alloreactive T and B cells and will apply Notch blockade as a strategy that separates GVHD from anti- tumor responses. I will first probe molecular events in cellular mediators of cGVHD to identify targets with mechanistic and broad relevance for cGVHD control. Second, I will define the evolution of humoral pathology following alloBMT and characterize its regulation by Notch signaling. The findings of this work will also be applicable to the area of solid organ transplant rejection and autoimmunity where Notch targeting has proven beneficial in the preclinical setting. I am a laboratory-based physician scientist at the University of Utah, clinically trained in hematology/oncology with a practice centered on adult blood and marrow transplant patients. My career development plan is focused on furthering cellular and molecular immunology foundations by acquiring advanced skills in next generation sequencing techniques, applied medical bioinformatics, and state-of-the-art genetic engineering. These proficiencies are now necessary for an independent laboratory-based investigator to successfully navigate the rapidly advancing genome sciences field and tailor them to individual projects. My career development plan directly complements and enhances the proposed research projects. I have assembled a mentoring and advisory team with expertise spanning all scientific and clinical areas pertinent to this proposal. The training I seek combined with the data we will collect will create a foundation for future R01 proposals and clinically relevant laboratory investigations focused on alloBMT. Throughout this career development plan, I am building on my prior training in hematology and transplant immunology to make strides toward an independent and high-impact research career. The proposed work is expected to provide a mechanism-based foundation for translating Notch blockade strategies into early clinical trials designed to maximize the therapeutic benefits of alloBMT by reducing cGVHD while preserving beneficial immune responses.
The chronic form of graft-versus-host disease (GVHD) is the major cause of late morbidity and mortality among survivors of allogeneic blood and marrow transplantation (alloBMT) and remains an area of unmet clinical need. Notch signaling can be successfully targeted in mouse models of alloBMT to alleviate acute and chronic GVHD without harming anti-tumor effects, with the maximum benefits of chronic GVHD control seen after immediate post-transplant Notch blockade. I will use Notch targeting as a platform to identify the earliest molecular changes in pathogenic mediators of chronic GVHD, uncover novel strategies for chronic GVHD control that maintain protective immunity and support translation of these findings into early clinical investigations to improve alloBMT outcomes.
