BM SUBPOPULATIONS TO REPAIR HUMAN ISLET INJURY AND SUPPORT ITS LONGEVITY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该项目的范围没有变化。 胰岛细胞分离后的高死亡率和功能障碍阻碍了胰岛移植的成功。因此，从分离过程中修复胰岛损伤和在体外长期维持胰岛作为新的胰岛资源的机会将代表显著的进步，并导致胰岛细胞移植的更广泛使用。骨髓在修复皮肤、神经元、心脏和肌肉损伤方面的成功利用使我们提出骨髓可以为这些挑战提供潜在的解决方案。在我们使用全骨髓与胰岛的共培养物的初步研究中，骨髓显示出增加胰岛功能/存活（超过六个月），刺激胰岛生长并在体外产生长期的胰岛素产生组织。我们推测，特定的骨髓细胞亚群可能是负责这些发现。我们还假设细胞外ATP、ATP受体（嘌呤受体P2 XR）和白细胞介素1 β（IL-1 β）参与骨髓诱导的胰岛损伤修复。在这个项目中，我们计划确定是否多个或单个特定谱系的骨髓细胞有助于胰岛重建。 我们将通过移植到NOD/SCID小鼠中来检查这些重建的胰岛是否具有足够的功能和体内血管形成。最后，我们将研究骨髓是否调节ATP，其受体P2 XR，IL-1？及其下游途径。该项目将有利于目前的胰岛移植方案，并将提供深入了解胰岛细胞死亡和再生的机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There has been no change in the scope of this project. The success of islet transplantation is hampered by the high rate of islet cell death and dysfunction after isolation. Therefore, the repair of islet damage from the isolation process and the opportunity to maintain islets long term in vitro as a new islet resource would represent significant advances and lead to a more widespread use of islet cell transplantation. Successful utilization of bone marrow in repairing skin, neuron, heart, and muscle injury led us to propose that bone marrow could offer a potential solution to these challenges. In our preliminary studies using co-cultures of whole bone marrow with islet, bone marrow was shown to increase islet function/survival (more than six months), stimulate islet growth and generate long-term insulin producing tissue in vitro. We hypothesize that specific subpopulations of marrow cells may be responsible for these findings. We have also hypothesized that extracellular ATP, ATP receptor (purinoreceptor P2XR), and interleukin 1beta (IL-1beta) are involved in bone marrow-induced repair of islet injury. In this project, we plan to identify whether multiple or single specific lineage marrow cells contribute to islet reconstitution. We will examine whether these reconstituted islets have sufficient function and vascularization in vivo as determined by transplantation into NOD/SCID mice. Finally, we will investigate whether bone marrow modulates ATP, its receptor P2XR, IL-1¿ and its downstream pathways. This project will have benefits for current islet transplantation protocols and will provide insight into the mechanisms of islet cell death and regeneration.