Evaluation of signals mediating beta-cell regeneration

 描述(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的综合征，因此糖尿病的治疗应该需要更换？细胞。在NOD小鼠和人类T1D患者中，存在与巨噬细胞表型相关的自身免疫易感性的遗传易感性，这有助于炎症的持久性和？细胞的破坏。在这里，我们提供的证据表明，一般情况下，巨噬细胞是胰腺再生的重要元素，尤其是？细胞的生成。此外，我们还证明了从NOD菌株分离的巨噬细胞有一种固有的诱导？细胞生成的能力。在这项提案中，我们将检验中心假设，即1型糖尿病是自身免疫和巨噬细胞无法产生对？细胞再生重要的细胞表型的综合效应。这项建议中描述的实验模型将使我们能够进一步研究小鼠巨噬细胞依赖的？细胞的增殖(特异性目标1)，以评估人类来源的 巨噬细胞诱导？细胞复制(特异性AIMS 2)，并确定巨噬细胞释放的人类？细胞生成所必需的假定因子(特异性AIMS 3)。免疫治疗显著降低了自身免疫相关细胞的增殖。因此，在没有自身免疫破坏的情况下，可能需要更多的治疗方法来刺激？细胞的再生，以恢复？细胞团。作为一种潜在的细胞治疗方法，从患者单核细胞产生的巨噬细胞可以被重新编程以促进？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T1D的充分理解和潜在的治疗。

 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.