Evaluation of signals mediating beta-cell regeneration

 说明（由申请人提供）：1型糖尿病是一种由胰岛素产生细胞数量减少引起的高血糖水平定义的综合征，因此糖尿病的治疗应该需要更换β-细胞。在NOD小鼠和人类T1 D患者中，存在关于巨噬细胞表型的自身免疫易感性的遗传倾向，这有助于炎症的持续和巨噬细胞破坏。在这里，我们提供的证据表明，巨噬细胞是胰腺再生的重要因素，特别是胰腺细胞的产生。此外，我们证明了从NOD菌株中分离的巨噬细胞具有固有的诱导巨噬细胞生成的能力。在这项提案中，我们将测试的中心假设，1型糖尿病是自身免疫和巨噬细胞无法产生一个细胞表型的细胞再生重要的综合效应。本研究的实验模型将使我们能够进一步研究小鼠巨噬细胞依赖性巨噬细胞的增殖（具体目的1），评估人源性巨噬细胞的增殖能力。 巨噬细胞诱导人β-细胞复制（具体目标2），并鉴定由巨噬细胞释放的对人β-细胞生成必需的推定因子（具体目标3）。免疫治疗显著降低了自身免疫相关的巨噬细胞增殖。因此，可能需要在不存在自身免疫破坏的情况下刺激β细胞再生的额外治疗方法来恢复β细胞团。作为一种潜在的细胞治疗方法，从患者的单核细胞产生的巨噬细胞可以被重编程以促进巨噬细胞再生。这项工作是一个高度优先的领域，因为它直接适用于我们对T1 D的充分理解和潜在治疗。

 DESCRIPTION (provided by applicant): Type 1 diabetes is a syndrome defined by high blood glucose levels caused by reduction in number of insulin producing cells, thus a cure for diabetes should entail replacement of ß-cells. There is a genetic predisposition for autoimmune susceptibility regarding macrophage phenotype in NOD mice and human T1D-patients, which contributes to persistence of inflammation, and ß-cell destruction. Here, we provide evidence that macrophages are important elements of pancreatic regeneration in general, and ß-cell generation in particular. Furthermore, we demonstrate that macrophages isolated from the NOD strain have an inherent inability to induce ß-cell generation. In this proposal, we will test the central hypothesis that Type1 diabetes is the combined effect of autoimmunity and the inability of macrophages to generate a cellular phenotype important for ß-cell regeneration. The experimental models described in this proposal will allow us to further study the macrophage-dependent ß-cell proliferation in mice (specific aims 1), to evaluate the ability of human-derived macrophages to induce ß- cell replication (specific aims 2), and to identify putative factors released by macrophages that are necessary for human ß-cell generation (specific aims 3). Immune therapy significantly reduces the autoimmune-associated ß-cell proliferation. Thus, additional therapeutic approaches that would stimulate ß-cell regeneration in the absence of autoimmune destruction may be needed for recovery of ß-cell mass. As a potential cell therapeutic approach, macrophages generated from patient's monocytes could be reprogrammed to promote ß-cell regeneration. This work is a high priority area as it is directly applicable to our full understanding and potential treatment of T1D.