Improved Targeting of Somatostatin Receptors for Pediatric Conditions

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PROJECT ABSTRACT Improved Targeting of Somatostatin Receptors for Pediatric Conditions Gigantism is a childhood developmental disorder whereby abnormally high levels of growth hormone result in excessive growth in both height and girth. The disorder can have serious physical complications including diabetes and loss of vision as well as social isolation. In the majority of cases gigantism is caused by pituitary adenomas which, when surgery is not an option, is treated with somatostatin receptor agonists to suppress growth hormone levels and provide symptom relief. Somatostatin receptors (SSTRs) are G protein coupled receptors (GPCRs) highly expressed in pituitary adenomas. Two analogues of the endogenous peptide, octreotide and lanreotide, were originally developed as SSTR2-selective, long-lasting peptide therapeutics for gigantism and other conditions. While they have proved successful, long-term side effects and other suboptimal properties drive the need for improved pharmaceutical interventions for gigantism. Much remains unknown about SSTRs and their pharmacology. To date, I have determined structures of SSTR2, however some questions of subtype selectivity remain unanswered without structures of the other subtypes. Much of the additional information about SSTR signaling partners is based upon downstream cellular assays, and much remains unknown about the relevance of SSTR subtype selectivity and signaling partner bias. Here I propose to utilize a combination of structural characterization with cryogenic electron microscopy (cryoEM), molecular dynamics simulations, and biochemical assays in order to characterize the selectivity, activation, and signaling profiles of SSTRs. The work will build upon my existing skillset in molecular simulations, modelling, and protein biochemistry while providing invaluable training in cryoEM data collection/processing and cell-based biochemical assays. Successful completion of this work will provide critical insight into the signaling landscape of the somatostatin receptor and the structural basis for both ligand-based and SSTR-subtype-based G protein selectivity. This will bridge several gaps in knowledge of SSTRs that should help in the development of improved, small molecule therapeutics that do not require repeated injections in children.