Project Summary/Abstract Insulin-mediated pseudoacromegaly (IMPA) is a rare insulin resistance syndrome that is distinct from other insulin resistance syndromes, as it leads to overgrowth and tall stature. Despite the handful of reported cases in the literature, there is no molecular or genetic explanation for this disease. Exome sequencing on an adolescent female with IMPA and her sibling and parents revealed that she carries two rare, potentially deleterious, variants in Fibroblast Growth Factor Receptor 1 (FGFR1) and 𝛽𝛽-Klotho (KLB), which form the receptor complex for Fibroblast Growth Factor 21 (FGF21). We hypothesize that these mutations explain the extreme insulin resistance, tall stature, and lipodystrophy-like phenotype seen in IMPA. To test the function of these FGFR1 and KLB variants in vivo, we used CRISPR/Cas9 genome editing to create a transgenic knock-in mouse line with these variants and corrected the FGFR1 and KLB mutations in an induced pluripotent stem cell (iPSC) line isolated from our proband with IMPA. In this study, we are proposing the following specific aims. In Aim 1, we will determine whether the metabolic and physical phenotype of IMPA mice (with mutations in Fgfr1/Klb) is a consequence of impaired FGF21 signaling. In Aim 2, we will determine if the insulin resistance seen in IMPA is due to impaired adipocyte function. In Aim 3, we will determine the mechanism of fatty liver disease in IMPA mutant mice. In addition to forming a functional genetic approach toward defining a novel insulin resistance syndrome, this four-year proposal outlines a comprehensive strategy for the principal investigator's career development in academic pediatric endocrinology. This strategy logically builds on the principal investigator's previous research experience and clinical training. After obtaining his MD, the principal investigator completed his residency training in general pediatrics, and fellowship in pediatric endocrinology. This proposal now focuses on expanding his scientific skills by attaining additional knowledge and practical research experience in studying a transgenic mouse model of a rare human insulin resistance syndrome. The career development goals will be achieved through a multi-faceted approach involving mentoring by Dr. David Ornitz (fibroblast growth factors and transgenic mouse models) and Dr. Fumihiko Urano (metabolic testing in mice), hands-on laboratory experience, scientific investigation, and training in genetics/genomics, biostatistics, scientific communication, and research ethics. This work will take place in a unique training environment comprised of complementary experiences at Washington University and St. Louis Children's Hospital. Successful completion of this career development award will result in the principal investigator's transition to an independent physician-scientist. Additionally, this work will contribute to a better understanding of the role that FGF21 plays in human insulin resistance, w...