The Human Pancreas Analysis Program for Type 1 Diabetes (HPAP-T1D) Abstract In 2016, the NIH NIDDK selected a multi-disciplinary team of investigators from three institutions (UPENN, Vanderbilt, University of Florida) to establish the pilot phase of the Human Pancreas Analysis Program (HPAP). Over the past three years, type 1 diabetes (T1D)-relevant tissues from more than 50 organ donors were profiled at the anatomic, physiologic, metabolic, immunologic, genomic and epigenomic levels. The resulting data were compiled and organized into the publicly accessible PANC-DB database and website. Here, we propose not only to continue, but to expand our efforts to apply and develop state-of-the-art technologies designed to phenotype and molecularly profile human tissues relevant to the etiology of T1D through a series of innovative efforts by six Cores. Core A (Pancreas Procurement and Islet Isolation) will procure/process pancreatic islets, pancreas and lymphoid organs, expand donor outreach (in collaboration with the well-established nPOD program) and increase the collection of non-pancreatic tissues. Core B (PhysiologicalPhenotyping)will provide a comprehensive metabolic profile and probe the key regulatory steps that govern hormone secretion from the major pancreatic endocrine cell types. Core C (Immunobiology) will develop an immune atlas of peripancreatic lymphoid populations, obtain transcriptomic profiles of the T1D- specific T cells, and perform immune repertoire profiling of B and T cells in association with single cell and antigen-specific cell approaches. Core D (Advanced Molecular Profiling) will perform RNAseq, ATACseq and DNA methylome analysis on sorted alpha-cell, beta-cell and exocrine cell population as well as scRNAseq and scATACseq and carry out whole genome sequencing. In addition, islet endocrine and major lymphocyte populations will be quantified precisely using flow CyTOF. Core E (Tissue Analysis & Biobanking) will analyze pancreatic tissue architecture and immune cell/epithelial cell interactions using multiple modalities including imaging mass cytometry, multi-spectral imaging and CODEX. Complete image data will be made available via PancreatlasTM and PANC-DB. Finally, Core F (PANC-DB, Data Analysis and Integration) will expand the PANC-DB resource by adding new features that will make the public web page even more useful, as well as add a Computational Biology and Data Science Unit for applying state-of-the-art analytical tools, allowing for the integration and visualization of generated datasets using different experimental modalities such as multi-spectral imaging and omics technologies. In addition, Core F will continue to expand its outreach activities, exemplified via the deposition of transcriptome and epigenome data into the Diabetes Epigenome Atlas (DGA). HPAP-T1D will be directed by an experienced, collaborative multi-PI team that confers weekly and will meet in-person on a biannual basis in coordination with NIDDK lea...