Objective
Our goal with this request for an nPOD renewal is to continue facilitating the community of type 1 diabetes (T1D) researcher’s efforts to answer the question of how the disorder develops; this, for the purpose of identifying a means to prevent and/or cure the disease, improve disease predition, as well as improve the lives of those living with T1D. We, as an organization, believe that nPOD’s ability to obtain and distribute relevant organ donor tissues is no longer of question and in fact, unmatched at an international level. Moving forward, we pose to continue procurement and distribution of high-quality human tissues from high priority organ donors (Aim 1). Specifically, we will provide unique service and support to the diabetes research community in order to facilitate ground-breaking investigator-initiated research questions (i.e., advancing our role as an accelerator and collaborative facilitator program). We will continue to maximize program efficiencies and importantly, continue to make nPOD tissues available to young/new investigators, industry, and experienced investigators with exploratory/high-risk innovative questions. We propose a new initiative to improve our geographic coverage of organ procurement organizations (OPOs) to ensure rapid procurement of organs to maximize their quality. However, we feel that our role at nPOD has evolved beyond logistics and organ distribution. In this renewal, our goal is to capitalize on the scientific success of nPOD as a nucleus for the T1D research community and a place where beta cell biologists, immunologists, basic scientists, and clinical investigators work collaboratively to solve translational and key questions regarding the etiology, progression, and intervention to halt T1D. In Aim 2 and 3, we will move beyond our highly successful Working Group model to enhance collaborative science and guide the research community to address a series of key questions, generated with assistance from the nPOD SAB. We expect that high value publications will continue to emanate from access to nPOD tissues and data. Perhaps most importantly, we expect that nPOD will continue to “re-write the textbooks” on how T1D develops. With this renewal request, we are positioning ourselves to identify additional disease phenotypic features and mechanisms in order to, ultimately, provide a comprehensive and unbiased understanding of human T1D. However, we also seek change and improved efficiency in order to expand on this progress, with enhanced interdisciplinary collaboration to improve our collective understanding of how and why T1D develops. The goal of leveraging this information is to inform therapeutic approaches for disease prevention and the optimization of disease modifying therapies. Importantly, the pursuit of novel strategies to prevent or cure T1D is not a new objective for nPOD, but this renewal puts forward a key shift with therapeutic discovery and development (based on an need to improve our understanding of key events relevant to disease prediction) representing not only long-term but now also, short-term goals for this program as we seek to address six key translational questions related to T1D. We continue to believe that this novel method for pancreas collection from organ donors, when combined with modern assessments of metabolic activity, immune function, clinical history, beta cell biology, developmental biology, as well as new areas of research (e.g., single cell multi-omics and live tissue studies on isolated islets as well as slices) will allow for major improvements in our understanding of the pathogenesis of T1D. nPOD, if renewed, should continue to play a critical role in seeing this goal achieved.
Background Rationale
The Network for Pancreatic Organ Donors with Diabetes (nPOD) mission is to improve our collective knowledge regarding the pathogenesis of type 1 diabetes (T1D) through the procurement, distribution, and study of human pancreata and disease-related tissues from organ donors with or at increased risk of developing T1D. Since the program’s establishment in 2007, nPOD has collected organs from over 600 donors, distributed these tissues across 22 countries to more than 320 projects (including both academic and industry settings), and supported over 350 publications to date. One of nPOD’s longest standing goals is to provide investigators the tissues for which they express the highest desire. Samples are provided free of charge (except for shipping costs) to approved investigators and/or companies worldwide; this with the goal of increasing research in T1D in human tissues (versus animal models). nPOD has also worked diligently to build a culture as well as an infrastructure for collaboration, with real time data sharing and integration. In this way, nPOD serves as a resource-based operation to the scientific community (i.e., an “accelerator”). Most importantly, knowledge gains from nPOD investigators have transformed our collective understanding of T1D pathogenesis and, we firmly believe, it has set an international standard for T1D team science. This said, this renewal application represents the most ambitious proposal for nPOD in the program’s history, as put forth in three Specific Aims. First, we will continue and expand on our well established and successful programmatic operations for islet autoantibody screening and procurement of organ donor cases in order to meet the needs and goals of independent investigators—including the establishment of a second nPOD organ processing and pathology core (OPPC) located on the U.S. west coast in order to reduce ischemia time for donors emanating from that geographic region (Aim 1). In Aim 2, we propose to expand our capacity for centralized hosting and sharing of data generated using nPOD samples. Beyond sample distribution, nPOD has strived to be “cutting edge” in terms of data sharing to investigators worldwide. Since the program’s last renewal, we have completed the first part of a new and improved nPOD Data Portal (V2.0) that will allow researchers to access and integrate the full gamut of available nPOD data/metadata from the administrative core and OPPC. The second part of the portal, which is currently under development, is focused on incorporating nPOD investigator-generated data to the system and adding contextual information to the data to quickly search for features of interest, bringing together datasets in many different formats that are often not easily shared, findable, or interoperable and making reusable the large collection of data being generated within the nPOD ecosystem. In Aim 3, we propose to advance hypothesis driven research seeking to address six key translational questions that are viewed as most pressing to the field of T1D research, which for their direct address, require programmatic expansion to expand nPOD’s influence, optimization, uniqueness, improved tissue and data access, and collaboration. These efforts, which were developed in consultation with our nPOD scientific advisory board (SAB), will inform on: 1) disease heterogeneity as it relates to age of onset, 2) pancreatic prohormone processing, 3) the exocrine pancreas, 4) testing of candidate therapeutics in live tissue culture systems, 5) identification of islet cell targets for in vivo imaging and drug delivery, and 6) clinical studies of T1D natural history as well as therapeutic trials. With this renewal, we are positioning ourselves to identify additional disease phenotypic features and mechanisms, to ultimately provide a comprehensive and unbiased understanding of human T1D.
Description of Project
The Network for Pancreatic Organ Donors with Diabetes (nPOD) mission is to improve our collective knowledge regarding the pathogenesis of type 1 diabetes (T1D) through the procurement, distribution, and study of human pancreata and disease-related tissues from organ donors with or at increased risk of developing T1D. Since the program’s establishment in 2007, nPOD has collected organs from over 600 donors, distributed these tissues across 22 countries to more than 320 projects (including both academic and industry settings), and supported over 350 publications to date. One of nPOD’s longest standing goals is to provide investigators the tissues for which they express the highest desire. Samples are provided free of charge (except for shipping costs) to approved investigators and/or companies worldwide; this with the goal of increasing research in T1D in human tissues (versus animal models). nPOD has also worked diligently to build a culture as well as an infrastructure for collaboration, with real time data sharing and integration. In this way, nPOD serves as a resource-based operation to the scientific community (i.e., an “accelerator”). Most importantly, knowledge gains from nPOD investigators have transformed our collective understanding of T1D pathogenesis and, we firmly believe, it has set an international standard for T1D team science. This said, this renewal application represents the most ambitious proposal for nPOD in the program’s history, as put forth in three Specific Aims. First, we will continue and expand on our well established and successful programmatic operations for islet autoantibody screening and procurement of organ donor cases in order to meet the needs and goals of independent investigators—including the establishment of a second nPOD organ processing and pathology core (OPPC) located on the U.S. west coast in order to reduce ischemia time for donors emanating from that geographic region (Aim 1). In Aim 2, we propose to expand our capacity for centralized hosting and sharing of data generated using nPOD samples. Beyond sample distribution, nPOD has strived to be “cutting edge” in terms of data sharing to investigators worldwide. Since the program’s last renewal, we have completed the first part of a new and improved nPOD Data Portal (V2.0) that will allow researchers to access and integrate the full gamut of available nPOD data/metadata from the administrative core and OPPC. The second part of the portal, which is currently under development, is focused on incorporating nPOD investigator-generated data to the system and adding contextual information to the data to quickly search for features of interest, bringing together datasets in many different formats that are often not easily shared, findable, or interoperable and making reusable the large collection of data being generated within the nPOD ecosystem. In Aim 3, we propose to advance hypothesis driven research seeking to address six key translational questions that are viewed as most pressing to the field of T1D research, which for their direct address, require programmatic expansion to expand nPOD’s influence, optimization, uniqueness, improved tissue and data access, and collaboration. These efforts, which were developed in consultation with our nPOD scientific advisory board (SAB), will inform on: 1) disease heterogeneity as it relates to age of onset, 2) pancreatic prohormone processing, 3) the exocrine pancreas, 4) testing of candidate therapeutics in live tissue culture systems, 5) identification of islet cell targets for in vivo imaging and drug delivery, and 6) clinical studies of T1D natural history as well as therapeutic trials. With this renewal, we are positioning ourselves to identify additional disease phenotypic features and mechanisms, to ultimately provide a comprehensive and unbiased understanding of human T1D.
Anticipated Outcome
Unlike the vast majority of hypothesis driven research programs funded by JDRF and The Leona M. and Harry B. Helmsley Charitable Trust (HCT), the Network for Pancreatic Organ donors with Diabetes (nPOD) serves as a resource to the scientific community (i.e., a research “accelerator”). As such, nPOD efforts have continually been subject to a series of operational questions such as, “Is the system running at maximal efficiency?; Is this working and if not, how can we correct it?; How can this effort be improved?; What is nPOD’s capacity?” and similar questions that are designed to constantly test the efficiency and efficacy of the program’s actions for meeting its goals. Various committees, designed for providing maximal operational efficiency, meet at regular intervals (e.g., an Executive Committee face-to-face retreat every 12 months, Operations Committee once per month, tissue prioritization committee [TPC] at least six times per year, our external Scientific Advisory Board [SAB] twice per year), or others as needed to optimize our operations. In maintaining this model, we anticipate that nPOD will continue its success in: 1) remaining “cutting edge”; 2) adapting to the growing needs of investigators in terms of the donor, tissue, and sample types we collect (e.g., isolated islets, live tissue slices, new forms of tissue processing, genetic data); 3) modifying the program to avoid overlap and build synergies with newly developed pancreatic procurement programs; 4) leveraging emerging technologies; 5) expanding functional bandwidth to increase organizational impact; 6) placing a priority on collaboration; and 7) facilitating data acquisition, sharing, and analysis. With this, nPOD has a unique track record of success in terms of meeting its operational goals and serving the needs of the greater research community. Perhaps most importantly, we anticipate that nPOD continue to be instrumental in putting to the test many of the long-standing dogmas regarding the pancreas in T1D, and generating a series of novel findings, many of which may lead to novel therapies and helped to decipher the disorder’s pathogenesis. This proposal describes the plans for nPOD for the next funding period. In developing such plans, we have intensively and diligently followed the recommendations of nPOD’s SAB; this, building on our organizational experience and data emerging from 15 years of running this program. We have certainly learned how to, and showed that nPOD readily adapts and corrects its course as needed to meet its goals and sustain progress over time. Hence, we expect that nPOD sample availability and data integration will continue to dramatically accelerate efforts to identify novel therapeutic targets and guide strategies for modulating immune and non-immune disease pathways in T1D. However, nPOD is prepared to expand beyond logistics and organ distribution. One of the major changes in this renewal application will be an even greater emphasis on research collaborations and partnerships, real time data sharing and integration; efforts that we believe are the way of the future and that we will continue to promote and expand. We expect that nPOD will continue to “re-write the textbooks” on how T1D develops enabling us to solve translational and key questions regarding the etiology, progression, and treatment of T1D with both immunomodulatory and islet cell targeting agents.
Relevance to T1D
Since the 1970s, when the notion that type 1 diabetes (T1D) represented an autoimmune disease was established, much of our knowledge regarding the disorder’s pathogenesis has been developed from analyses of serum as well as peripheral blood lymphocytes from patients with the disorder. Utilizing these tissues, investigators discovered evidence of both humoral and cell-mediated autoimmunity to islet cell antigens, identified the gene variants conferring susceptibility to the disease, uncovered evidence of compromised immunoregulatory responses, and much more. At the same time, efforts involving animal models of diabetes, especially non-obese diabetic (NOD) mice, were also utilized for this goal, to perhaps an even greater degree (in terms of sheer numbers of studies) in an attempt to define how T1D develops. From these collective efforts, many “dogmas” were generated regarding the disorder’s pathogenesis and natural history. However, recent efforts, largely emanating from the network of Network for Pancreatic Organ donors with Diabetes (nPOD) investigators studying the human pancreas and its insulin producing beta cells (the actual target of T1D-directed autoimmunity), have resulted in a situation where multiple long-standing dogmas are actively undergoing major readdress. Indeed, many in the T1D research community have accepted the challenge to re-examine many early dogmas surrounding T1D. In terms of knowledge pertaining to its pathogenesis, the field of T1D research is undergoing active change, and much of this has derived, over the 15 years, from efforts related to the nPOD program. Perhaps most notably, nPOD-based efforts have impacted at least six representative areas regarding T1D pathogenesis: 1) insulitis; 2) the natural history of pancreatic pathology in T1D (both prior to onset, at onset, and in long-standing disease); 3) beta cell dysfunction; 4) a potential role for the exocrine pancreas in T1D development; 5) T1D heterogeneity; and 6) natural history models of T1D development. Moreover, with its success, nPOD has served a model system for how organizations and academic programs can work with U.S. Organ Procurement Organizations (OPOs) across multiple additional organ donor-based research programs that have been developed in the diabetes community (e.g., HPAP T1D and type 2 diabetes [T2D]), for other disease-based research disciplines, and even in understanding normal human biology/physiology (e.g., HANDEL-P/I, HuBMAP). We believe this programmatic model for collection of transplant-quality pancreas (and other tissues) from organ donors, when combined with modern assessments of metabolic activity, immune function, clinical history, beta cell biology, developmental biology, as well as cutting-edge areas of research will allow for major improvements in our understanding of T1D pathogenesis, providing an improved foundation for drug discovery and development. Our goal with nPOD is to continue to facilitate the community of T1D researcher’s efforts to answer the question of how the disorder develops; this, for the purpose of identifying a means to prevent and/or cure the disease as well as improve the lives of those living with T1D.