Elucidating the Role of the FGFR1 Signaling Pathway in the Intersection of Reproduction and Metabolism - PROJECT SUMMARY The overarching goal of this proposal is to investigate the role of the FGFR1 signaling pathway in the intersection between reproduction and metabolism. Even though reproduction and metabolism have been intricately linked, the underlying mechanisms that govern this intersection are not clearly understood. One pathway that could bridge those two domains is the fibroblast growth factor receptor 1 (FGFR1) signaling pathway. Regarding reproduction, FGFR1 is crucial for the development of neurons that secrete Gonadotropin Releasing Hormone (GnRH), a hormone that heralds the onset of human sexual maturation, with rare deleterious heterozygous FGFR1 variants leading to pubertal failure. Regarding metabolism, attenuation of FGFR1 signaling leads to diabetes in mice and insulin resistance in humans. Activation of the FGFR1 signaling pathway improves metabolic health in animal models and humans. One potential explanation of how the suppression/activation of the same receptor leads to such disparate phenotypes is through the action of the different FGF ligands and co- receptors. The Applicant has hypothesized that while FGFR1 is essential for both reproduction and metabolism, distinct FGF ligands and their interactions with specific co-receptors will impart phenotypic specificity: the paracrine FGF8 ligand and HS6ST1 co-receptor will be specific for reproduction, while the endocrine FGF21 ligand and KLB co-receptor will be specific for metabolism. To test this hypothesis, the PI will: (i) conduct a unique Recall-by-Genotype (RbG) study and in-depth neuroendocrine (Aim 1) and metabolic (Aim 2) phenotyping in humans carrying rare deleterious FGF-related genetic variants; and (ii) examine the FGF ligand specific effect on FGFR1 signaling in cells related to reproduction and metabolism. This application outlines a comprehensive 5-year training program designed to foster the Applicant’s mentored career development in translational research. Completion of this project will serve as an ideal training vehicle for the Applicant’s training in neuroendocrine and metabolic investigation. To achieve this goal, she has selected mentors with complementary expertise: Dr. Stephanie Seminara [mentor, Chief of the Reproductive Endocrine Unit at Massachusetts General Hospital (MGH)] is a world expert in reproductive neuroendocrine physiology and human genetics of reproductive disorders; Dr. Steven Grinspoon (co-mentor), Chief of the Metabolic Unit, MGH, is a renowned expert in studies of hormonal function, nutrient trafficking, and the metabolic consequences of fat redistribution in a broad number of disease conditions. This award will effectively prepare the Applicant to launch a successful translational research career, with an emphasis on intersection between reproduction and metabolism, a key NICHD research priority area. The Applicant's career development plan involves rigorous coursework and seminars, hands-on experience, and guidance from advisors with diverse scientific backgrounds. In summary, the expertise gained during this award will form the basis for the Applicant's independent academic transdisciplinary career as a physician-scientist.
