Critical obstacles have impeded studies of the pathobiology of pancreatitis. First, molecular approaches are difficult to apply in primary acinar cells, which are short-lived and difficult to transfect using chemical or physical methods for gene delivery using plasmid DNA. Second, it is difficult to assess whether findings in animal models are relevant to human disease because the lack of availability of human tissues. This includes freshly isolated human acinar cells as well as tissues with pancreatitis. However, significant advances have been made in recent years in overcoming these obstacles. Success has been achieved in transfecting primary acinar cells using viral vector-mediated gene delivery methods. Furthermore, we and others now find that a plentiful supply of functional human acinar cells can be generated as a byproduct of tissue isolation used for islet transplant programs. The Vector and Human Acinar Core will provide Program researchers with the tools, i.e., viral vectors, human acinar cells, transduction methods for mouse and human cells) needed to perform their specific mechanistic studies and to extend their findings from animal models into human pathology. The Core comprises 3 sub-Cores. The Vector sub-Core will design, construct, and produce adenoviral and lentiviral vectors bearing transgenes of interest for individual projects (Aim 1). The Transduction sub-Core will determine conditions and perform efficient viral transduction of acinar cells (Aim 2). The Human acinar sub-Core will be responsible for isolating human acinar cells and using these cells in ex-vivo models of pancreatitis (Aim 3). The Core will also provide training of project investigators in acinar cell viral transduction and human cell isolation (Aim 4). Centralizing the proposed tasks in one Core will reduce costs through sharing of vectors, transduced cells and human acinar cells and also by applying standardized techniques for cell isolation and culture and genetic transduction. Furthermore, the availability of centralized reagents and standardized techniques to be provided to all Program investigators will help to ensure consistency, reliability, and reproducibility of experimental results. The Core will also provide training of project investigators in virus handling, acinar cell transduction and human cell isolation.
Vector and Human Acinar Core: Narrative The Vector and Human Acinar Core is devoted to providing to Program investigators difficult to develop and use techniques, such as viral transductions, to regulate the expression of specific genes in both mouse and human primary acinar cells. This ability will allow the scientists in the Program to reveal undiscovered pathways involved in causing pancreatitis that could not be done otherwise. The human aspect of the Core is devoted to another challenge in the pancreatitis research field: making sure that the pathways of pancreatitis we see in mice are relevant to human disease. Thus, the Core will be devoted to obtaining and maintaining functional human acinar cells for experiments including the ones that use viral vectors.
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