PROJECT SUMMARY / ABSTRACT The Arkansas Integrative Metabolic Research Center (AIMRC) is a Phase I COBRE at the University of Arkansas at Fayetteville (04/01/2021-02/28/2026; PI: Dr. Kyle P. Quinn). The scientific theme of the AIMRC is to understand the role of cell and tissue metabolism in disease through biomedical research involving advanced imaging, bioenergetics, and data science. The long-term objective of the AIMRC is to establish a sustainable interdisciplinary research center that can support biomedical research at the U of A, grow the emerging strength in metabolic research on campus, and collaborate with other COBRE centers, such as the MaineHealth Institute for Research. The overall goal of this administrative supplement is to characterize the impact of a chimeric superFGF1-FGF21 protein on dysregulated metabolism diseases as it is now well accepted that there are numerous factors contributing to a patient being considered at high risk for cancer development, with dysregulated metabolism being the most prominent. Modulating an individual's metabolic condition presents a potential treatment option to mitigate the risk of cancer development. The proposed study introduces a chimeric Fibroblast Growth Factor hyperstable non-heparin binding FGF 1 (superFGF1) and the C-terminal terminal tail of FGF21, named superFGF1-FGF21 C-terminal tail, harnessing the metabolic modulation properties of both FGF21 and the FGF receptor binding capabilities of FGF1 and FGF21. The metabolic cytokine, FGF21, a non- heparin binding cytokine, modulates lipid and glucose oxidation activates mTOR signaling, and requires alpha/beta Klotho co-receptors for FGF receptor binding. FGF1, on the other hand, is known for its ability to modulate metabolism and interact with all known isoforms of FGFR, which complements FGF21. The hypothesis is that combining the metabolic stimulatory activity of FGF21 with the FGFR binding capacity of FGF1 in a hyper-stable superFGF1-FGF21 chimera can yield a potent regulator of metabolic condition. The development of this recombinant chimera, confirmed through successful overexpression and purification with superior stability in preliminary data, is positioned to diffuse through the heparin-rich extracellular matrix, reaching distant organs in a hormone-like manner. The proposed study outlines two main objectives: 1) Refine the superFGF1-FGF21 chimeric protein and characterize its therapeutic capabilities to regulate adipogenic differentiation and lypolysis; 2) Assess the therapeutic potential of the FGF1-FGF21 chimera in a model of Diamond Blackfan Anemia (DBA), a ribosomopathy characterized by dysregulated protein metabolism and predisposition to cancer growth. A multidisciplinary team with expertise in structural biology, FGF biology, adipose metabolism, protein synthesis, and two-photon microscopy has been assembled. We expect that the results of this pilot study will lay the foundation for future multi-PI R01 submissions and active collaborative research between the two teams to successfully decipher the correlation between metabolic dysfunction and cancer.

PROJECT NARRATIVE The overall goal of this administrative supplement is to explore the potential of a novel artificially designed hybrid growth factor to regulate the metabolism of fat and cancer cells. The collaborative efforts of the COBRE investigators at AIMRC and MHIR are expected to yield valuable clues in the rational design of therapeutics against metabolic dysfunction leading to the onset of cancers.