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The Role of Hedgehog and Enteric Neural Crest Cell Reprogramming in Neuroendocrine Differentiation

Sponsored by National Institute of Diabetes and Digestive and Kidney Diseases

Active
$106.4K Funding
2 People
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Abstract

PROJECT SUMMARYDespite increasing diagnoses gastroenteropancreatic neuroendocrine tumors (GEP-NETs) remain poorlyunderstood both in relation to their molecular pathogenesis and cells-of-origin. My recent work using transgenicmice demonstrated for the first time the involvement of enteric neural crest-derived cells (ENCCs) inneuroendocrine differentiation and tumor development driven by Men1 gene deletion. Consistent with its role incell fate patterning Hedgehog signaling was implicated in neuroendocrine reprogramming of ENCCs. Meninencoded by the MEN1 gene has been shown to regulate Hedgehog signaling in mouse models of pancreaticNET development however reciprocity between menin and Hedgehog has yet to be studied in ENCCs. Thisproposal aims to address whether loss of menin in ENCCs drives acquisition of the neuroendocrine cell fate withlineage commitment being actively modulated by Hedgehog signaling. My goals are to define the cells-of-origin for MEN1 GEP-NETs and to decipher the role of Hedgehog in driving neuroendocrine cellpatterning. I will combine my experience using novel transgenic mouse models and ex vivo tissue culturetechniques with state-of-the-art single cell and spatial transcriptome profiling to define the contribution of ENCCsto neuroendocrine differentiation and GEP-NET development. I hypothesize that reciprocal signaling bymenin and Hedgehog drives ENCC reprogramming and gives rise to hyperplastic neuroendocrine cellswith tumorigenic potential. This Research Plan will determine whether MEN1-associated GEP-NETs originatefrom reprogrammed ENCC populations (Aim 1) and decipher the role of Hedgehog signaling in neuroendocrinereprogramming of MEN1 GEP-NETs (Aim 2). During the mentored K01 award period I will work closely with myprimary mentor Dr. Juanita Merchant and co-mentor Dr. Megha Padi distinguished experts in gastrointestinalbiology and single cell analysis respectively to develop the skillset to accomplish my research and careerobjectives. My Career Development Plan will facilitate my goal of becoming a productive independentinvestigator by combining rigorous didactic training and formal mentorship under a team of faculty who bringestablished expertise in cell and molecular biology gastrointestinal physiology large genomic data analysis and3-D organoid systems. Finally the breadth of career development resources and extensive shared researchfacilities at the University of Arizona make it an ideal environment for me to carry out the proposed researchproject and achieve my career objectives. By leveraging innovative GEP-NET models and cutting-edgesequencing methods this award will enable me to establish a state-of-the-art research program with the long-term goal of defining the cellular signals that govern enteric neuroendocrine cell fate.

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