The proposed Mentored Research Scientist Development Award (K01) will provide the candidate, Dr. Terri Iwata, with the necessary training, skills and experience to become an independent comparative biomedical research scientist focused on defining the metabolic networks that regulate immune system development and function. Defects in cellular metabolic capacities are associated with lymphocyte dysfunction and developmental blocks. The mammalian target of Rapamycin (mTOR) signaling pathway responds to cellular nutrient and energy levels to coordinate cell metabolism, growth and proliferation. mTOR inhibitors are used clinically as immunosuppressive and chemotherapeutic agents, and are being investigated for use in agerelated diseases. The immunomodulatory role of mTOR has been attributed to its effects on T cells; however, very little is known about the role of mTOR in B cell metabolism, development, and function. The central hypothesis for the proposed research, based on strong preliminary findings, is that mTOR signaling is critical for regulating B cell development and function by controlling cellular metabolism at key stages of B cell development and maturation. The proposed research is highly significant because it will elucidate the underlying mechanisms of currently used mTOR-targeting drugs and their potential side effects. Completion of these studies represents the first step towards designing and refining future therapies with targeted effects on the mTOR pathway.
The research aims of this project are: 1) To define the role of mTOR signaling in modulating pre-B cell development; 2) To define mTOR signaling-dependent responses in pre-B cells; and 3). To determine the role of mTOR signaling in modulating peripheral B cell development and function. Mouse models in which mTOR signaling has been altered specifically in B cells will be utilized to determine consequences on B cell development and function (Aims 1 and 3), and gene expression analysis, metabolic flux, and metabolomic analysis will be used to determine the downstream effects of mTOR signaling in B cells (Aims 2 and 3). To accomplish these aims, Dr. Iwata will build on her background in molecular and cellular biology by developing expertise in immunological techniques, cellular metabolic assays, and the generation and utilization of murine models. The University of Washington (UW) offers the ideal location to achieve these research and training goals. Dr. Iwata's mentor is a highly-successful independent investigator with expertise in immunology, cellular metabolism, and cancer biology. The UW, one of the premier research universities in the country, boasts extensive resources, facilities, and world-class research faculty to facilitate the completion of te proposed research and career development activities. Completion of the proposed activities will provide Dr. Iwata with the critical knowledge, experience, and skills required to be an R01-funded independent comparative biomedical research scientist.

Public Health Relevance

Disruption of cellular metabolic processes can alter B cell development and function, leading to impaired immune responses. The mTOR signaling pathway integrates cellular nutrient and stress signals to regulate many physiological processes, and drugs that target the mTOR pathway are used clinically as immunosuppressive and chemotherapeutic agents, yet their effects on B cell metabolism, development and function remain largely unknown. The proposed research will elucidate the role of the mTOR signaling pathway in B cell development and function with the goal of enabling future development and refinement of drugs that target this pathway in the treatment of disease.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Research Scientist Development Award - Research & Training (K01)
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Special Emphasis Panel (ZRG1)
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Fuchs, Bruce
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University of Washington
Veterinary Sciences
Schools of Medicine
United States
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Centini, Ryan; Tsang, Mark; Iwata, Terri et al. (2018) Loss of Fnip1 alters kidney developmental transcriptional program and synergizes with TSC1 loss to promote mTORC1 activation and renal cyst formation. PLoS One 13:e0197973
Iwata, Terri N; Ramírez-Komo, Julita A; Park, Heon et al. (2017) Control of B lymphocyte development and functions by the mTOR signaling pathways. Cytokine Growth Factor Rev 35:47-62
Iwata, Terri N; Ramírez, Julita A; Tsang, Mark et al. (2016) Conditional Disruption of Raptor Reveals an Essential Role for mTORC1 in B Cell Development, Survival, and Metabolism. J Immunol 197:2250-60