Viral insulin-like peptides and their unique activities on mammalian insulin/IGF-1 system - PROJECT SUMMARY/ABSTRACT In mammals, insulin primarily regulates metabolism while insulin-like growth factor-1 (IGF-1) stimulates growth, proliferation and differentiation. Aberrant production of IGF-1 is connected with different human diseases including growth disorders such as Laron syndrome, acromegaly and Graves' orbitopathy as well as thyroid eye disease (TED) and the early stages of diabetic nephropathy. In addition, circulating levels of IGF-1 are increased in cancer patients and IGF-1 receptor (IGF1R) expression is upregulated in various tumor types. Although the IGF1R system plays a key role in tumor progression and has been one of the most intensively investigated molecular targets in cancer research, previous clinical attempts to develop IGF1R inhibitors have largely failed. Thus, there is a critical knowledge gap regarding the underlying mechanisms of IGF1R inhibition and an urgent need to develop novel IGF1R inhibitors. The data generated through my K01 grant has expanded the family of insulin/IGF-like hormones and provided us a new tool to probe this complex system: viral insulin/IGF-1-like peptides (VILPs). Previously, we chemically synthesized these VILPs and characterized their function on the insulin receptor (IR)/IGF1R system using in vitro and in vivo assays. While most of the VILPs are natural agonists of the IR and IGF1R, we showed that two VILPs in Mandarin fish ranavirus (MFRV) and Lymphocystis disease virus-1 (LCDV1) are highly specific and potent antagonists of the IGF1R. This discovery has opened up new avenues for understanding and studying IGF1R inhibition. The overarching goal of this proposal is to examine unique antagonist effects of MFRV and LCDV VILPs on the IGF1R to elucidate the underlying structural and molecular mechanisms of the IGF1R inhibition. Our central hypothesis is that the VILPs will inhibit IGF1R signaling and IGF-1 related proliferation function via their unique interaction with the IGF1R, differentially regulating post-receptor signaling pathways and IGF1R gene expression. We will test this hypothesis based on two independent Aims. In Aim 1, we will test the hypothesis that VILPs engage with human IGF1R in a unique way, recruit different substrates to the receptor and modify post-receptor signaling while directly regulating IGF1R gene expression. We expect to determine the molecular and structural mechanisms of the hIGF1R antagonism in vitro. In Aim 2, we will test the hypothesis that VILPs will specifically inhibit IGF1R signaling in vivo without affecting IR signaling and decrease IGF-1 mediated growth without affecting glucose metabolism. These findings will define the effects of VILP-mediated IGF1R inhibition using two in vivo models of IGF-1 mediated growth and IGF-1 mediated tumor progression. This proposal is built on the conceptual innovation based on our exciting discovery of the VILPs and their unique effects on IGF1R. We propose using cutting-edge techniques and if proven right, these studies will transform our understanding of the IGF1R inhibition and function as a proof-of-principle for the introduction of peptide-based inhibitors of the IGF1R into the framework of human disease research.
