Relative to resting lymphocytes, both activated lymphocytes and cancer cells exhibit a unique shift in cell metabolism from oxidative phosphorylation, which efficiently produces energy, to aerobic glycolysis, which generates bio-precursors (such as lipids, amino acids, and nucleotides) required to fuel cell division. An understanding of the factors that control this metabolic switch (termed Warburg effect) is highly significant because it could lead to novel strategies to selectively block lymphocyte activation in autoimmune disease, and/or inhibit cancer cell survival. In this application, we propose to investigate a novel protein called Folliculin Interacting protein-1 (Fnip1) which our studies suggest is essential for maintaining metabolic balance during energy and nutrient stress such as during lymphocyte activation, nutrient restriction, and oncogene activation. We identified an innovative new strain of mice lacking Fnip1 in a chemical mutagenesis screen, based on the complete absence of B lymphocytes in peripheral blood. Fnip1 null mice have blocks in pre-B cell and invariant natural killer T (iNKT) cell development at stages where the cells normally undergo massive division dependent on c-Myc, an oncogene deregulated in many cancers in humans. Remarkably, loss of Fnip1 also protects against pre-B cell lymphoma induced by c-Myc in a mouse model of Burkitt's B cell lymphoma. Although the functions of Fnip1 are unknown, it interacts with Folliculin (a protein of unknown function) and the master metabolic regulator AMP kinase, an energy sensing molecule that stimulates energy production in response to energy stress and inhibits energy-consuming anabolic processes regulated by mammalian target of rapamycin (mTOR). Our long-term goals are to determine how Fnip1 functions to control the development, activation, metabolism, and transformation of lymphocytes.
Our Specific Aims are: (1) To define the roles of Fnip1 in pre-B cell development and metabolism. We will utilize metabolomic, metabolic flux analysis, and transcriptomic approaches to determine whether loss of Fnip1 inhibits the Warburg effect; (2) To determine the importance of Fnip1 in B cell lymphoma survival and sensitivity to metabolic stress and chemotherapeutic agents. We will conditionally delete Fnip1 in primary murine B cell lymphomas and will determine consequences on tumor cell survival and signaling in response to nutrient deprivation and chemotherapy; and (3) To delineate the molecular functions of Fnip1 in autophagy and mTOR signaling pathways. We will use biochemical and genetic approaches to determine whether Fnip1 is essential to turn off mTOR mediated nutrient consumption, and turn on autophagy (self-digestion of organelles to generate nutrients) in response to nutrient deficit. These studies will address our overall innovative hypothesis that inhibition of Fnip1 disconnects the essential link between anabolic cell growth and aerobic glycolysis, by permitting activated lymphocytes and/or tumor cells to grow in the absence of sufficient energy and bio- substrates, resulting in nutrient exhaustion and cell death.
The proposed research is relevant to public health because it will test the efficacy of inhibiting Fnip1 as a strategy to neutralize auto-reactive immune cells i autoimmune diseases and/or kill cancer cells in leukemia and lymphoma patients. The proposed studies are highly relevant to the NIH mission because they predict clinical benefits of inhibiting Fnip1 in autoimmune diseases and cancer, as well as in metabolic diseases such as obesity, diabetes, and muscular dystrophy.
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