PROJECT SUMMARY This objective of this Research Supplement to Promote Diversity in Health-Related Research (PA-21-071) is to provide a mentored experience in basic and translational science for Dr. Callisia N. Clarke. The purpose of the parent R01 (DK052913; Raul Urrutia, MD; contact PI; and Gwen Lomberk, PhD; PI) is to investigate the role of epigenetic regulation in pathophysiological mechanisms underlying pancreatic diseases and to understand how potentially druggable epigenomic landscapes, identified from patient-derived material, are linked to development of preneoplastic and neoplastic diseases of the pancreas. Cell growth regulation that is vital for pancreatic development and homeostasis is altered in most pancreatic disease states, including cystic lesions, IPMN, and pancreatic cancer. Research conducted in the mentors' laboratories on patient derived tissue encompasses a multi-parametric integrative analysis of ChIP-seq on multiple histone modifications, RNA-seq, and DNA methylation to define epigenomic signatures for human pancreatic ductal adenocarcinoma (PDAC) subtypes, which can predict their relative aggressiveness and survival[1]. However, little is known about the impact of epigenetic regulation on the development and progression of pancreatic neuroendocrine tumors (PNET). PNETs are rare tumors with significant heterogeneity in clinical presentation and prognosis. Functional PNET (F-PNET) are associated with hormone secretion causing a clinical syndrome, while non-functional (NF-PNET) tumors are not associated with hormone-driven symptoms. This supplemental application is designed to expand studies of the parent grant beyond PDAC and characterize modifications in gene expression mediated by noncoding RNA (ncRNA) in PNET. Our Central Hypothesis is that epigenetic mechanisms, at the level of ncRNA, lead to silencing of the functional phenotype of PNET, yielding NF-PNET. Our specific aims are: 1. To determine the distinct epigenomic signatures that exist between F-PNET and NF-PNET using ncRNA sequencing analysis and 2. To evaluate the impact of ncRNA signatures on NF-PNET treatment response, disease progression, and patient survival. Dr. Clarke will be mentored by an outstanding team of investigators with complementary expertise in the areas of epigenomics and bioinformatics. The mentoring/career development plan will focus on research design, methodology, and data analysis. The proposed research aligns with the parent R01 study in conceptual framework and necessary expertise. Furthermore, this Research Supplement will help in our commitment to promote the growth of one of our minority researchers in health sciences. Results from this study will serve as preliminary data for a NIH K08 award. Dr. Clarke's long-term goal is to develop her independent research program in PNET tumorigenesis and to identify potentially actionable epigenetic pathways to interrupt progression of this disease.