This Funding Opportunity Announcement (FOA) invites cooperative agreement applications that will contribute to a higher resolution understanding of the organization of the human pancreatic tissue environment by describing the composition and function of important components of the pancreatic islet and peri-islet tissue architecture, the cell-cell relationships and means of communications used by cell types and cell subtypes within the pancreatic tissue ecosystem, and the contribution of adjacent tissues to islet cell function and dysfunction. Successful projects will integrate the Human Pancreas Analysis Consortium (HPAC) that is part of the Human Islet Research Network or HIRN (https://hirnetwork.org/). HIRN’s overall mission is to support innovative and collaborative translational research to understand how human beta cells are lost in T1D, and to find innovative strategies to protect and replace functional beta cell mass in humans. This FOA will only support studies with a primary focus on increasing our understanding of human tissue structure and function, and human disease biology, as opposed to exploring the biology specific to any animal models.
Much remains to be learned about the contribution of the human pancreatic tissue environment to normal islet cell function and to Type 1 diabetes pathogenesis in humans. Our inability to access the target organ in living individuals, or to extract meaningful biological information from fixed cadaver donor pancreata, still limits our knowledge of pancreatic tissue architecture and function to observations from rodent models. As a result, our understanding of the cellular diversity of the human pancreatic tissue environment and the peri-islet niche, and of the mechanisms by which cell types and tissue compartments communicate with one another to modulate complex endocrine functions or contribute to the initiation of autoimmunity in T1D, remains limited. This profound knowledge gap impairs our ability to identify novel therapeutic targets, to deliver therapeutic cells or compounds to specific pancreatic sub-compartments, or to develop highly-relevant disease modeling platforms with structural and functional characteristics that closely mimic the endogenous human islet niche for drug discovery and drug testing.
The past few years have witnessed the development of powerful technologies that can be applied to the qualitative and quantitative exploration of fixed and live human tissue preparations. Single cell analyses of dissociated cells from human pancreata can produce detailed transcriptomics (RNA-seq), epigenomics (ATAC-seq), and multiplexed proteomics (CyTOF) profiles to explore tissue cell diversity with unprecedented resolution. Complex molecular signatures can be used to build highly-multiplexed imaging-based assays (Imaging Mass Cytometry, CODEX, sequential RNA-FISH) that, when combined with tissue-scanning/capture protocols and network analysis algorithms, can lead to a spatially resolved characterization of tissues and the generation of new hypotheses regarding cell-cell interactions. In addition non-targeted analytical methods can allow for direct omics measurements in situ using fixed tissue preparations. For example, single-nucleus RNA sequencing from snap frozen pancreata can be combined with 3D spatial reconstruction techniques to report on transcriptional activity and cellular diversity in specific pancreatic tissue niches and cell subtypes. Other unbiased techniques such as MALDI can be combined with laser capture protocols to provide direct and unbiased proteomics, lipidomics and metabolomics measurements on archived human pancreatic specimens with sub-islet resolution. Finally, progress in the culture of human pancreatic tissue slices allows for the study of individual cell function and cell-cell interactions in the context of a live 3D tissue environment in which components of the cytoarchitecture are at least partially preserved. Perfused pancreatic tissue slices and other in vitro platforms such as microfluidics-coupled islet bio-mimetics or islets-on-a-chip, can now be used to complement hypothesis-generating omics measurements with mechanistic studies in the context of live tissue or tissue-like experimental systems.
Application of these technologies to human pancreatic tissues is already yielding intriguing observations about the potential contribution of cellular components of the broader pancreatic niche to islet cell function and dysfunction. Yet much remains to be learned about the cell-cell communications, paracrine regulations and signaling pathways underlying these regulatory functions, and the contribution of various pancreatic cell types to T1D and T2D pathogenesis. Likewise, many cell conditions and regulated processes that have been shown in other tissues to play a critical role in cell function, homeostasis and disease development remain relatively unexplored in the pancreatic cell types that are known to contribute to the emergence of a diabetes phenotype.
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