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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这个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，分离过程中胰岛损伤的修复以及作为新的胰岛来源在体外长期保持胰岛的机会将代表着重大进展，并将导致胰岛细胞移植的更广泛应用。骨髓在修复皮肤、神经元、心脏和肌肉损伤方面的成功应用使我们提出，骨髓可以为这些挑战提供潜在的解决方案。在我们使用全骨髓和胰岛共培养的初步研究中，骨髓被证明在体外可以增加胰岛功能/存活(超过6个月)，刺激胰岛生长并产生长期的胰岛素产生组织。我们推测，这些发现可能与特定的骨髓细胞亚群有关。我们还假设细胞外ATP、ATP受体(嘌呤受体P2XR)和白介素1β(IL-1β)参与了骨髓诱导的胰岛损伤修复。在这个项目中，我们计划确定多个或单个特定谱系的骨髓细胞是否有助于胰岛重建。我们将通过移植到NOD/SCID小鼠体内来检查这些重组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对ATP、其受体P2XR、IL-1及其下游通路进行调节。该项目将对目前的胰岛移植方案有所裨益，并将为深入了解胰岛细胞死亡和再生的机制提供依据。

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.