TRANSGENIC MODEL OF INDUCIBLE DIABETES

描述(由申请人提供)： 我们建议建立一种快速诱导型糖尿病转基因模型。这项建议的主要目的是确定成年小鼠体内产生胰岛素的β细胞的来源。在这些动物中，无论是在发育过程中，还是在出生后生长期间，或在成年动物中，注射诱导剂后，都会诱导完全或部分选择性地破坏胰岛β细胞。这些动物不会被设计用来研究I型糖尿病的发病机制和自身免疫机制，也不会被用来研究炎症；相反，它们将有助于准确评估成人胰腺再生过程中的胰岛(β细胞)新生，该过程应该遵循诱导剂的治疗。它们还将用于重建试验，以确定注射的干细胞/祖细胞的分化潜力，无论是静脉注射。或直接进入胰腺，来自胰腺或胰腺外组织(例如，肝、神经或造血干细胞，或ES细胞克隆)。顺便说一句，这个转基因模型将代表着一个独特的工具，除了它们产生胰岛素的作用外，它还将成为研究β细胞参与胰腺动态平衡的独特工具。其具体目的是：1)建立β细胞消融的转基因模型；2)研究β细胞的再生；3)进行移植细胞的体内克隆重建实验。除了器官生长和维持的基本过程外，这项研究还可能对糖尿病的细胞替代疗法以及与使用胚胎或成人干细胞有关的所有伦理问题产生影响。一旦产生，这些转基因菌株将被放入“公共”Beta细胞生物学联盟(BCBC)小鼠储存库，以便广泛的科学界使用，就像我们过去对其他转基因小鼠所做的那样

DESCRIPTION (provided by applicant): We propose the generation of a transgenic model of rapid inducible diabetes. The major aim of this proposal is to determine the origin of insulin-producing beta-cells in adult mice. In these animals, complete, or partial, selective destruction of pancreatic beta-cells will be induced, either during development, during postnatal growth or in adults, upon administration of an inducer drug. These animals will not be engineered to study the pathogenesis of Type I diabetes and the autoimmune mechanisms, nor inflammation; rather, they will be useful to accurately assess islet (beta-cell) neoformation in adult pancreas during the regeneration process that should follow the treatment with the inducer agent. They will also be used in reconstitution assays to determine the differentiation potential of injected stem / progenitor cells, whether i.v. or directly into the pancreas, derived either from pancreatic or extra-pancreatic tissues (e. g. hepatic, neural or hematopoietic stem cells, or ES cell clones). Incidentally, this transgenic model will represent a unique tool to study the involvement of beta-cells in pancreas homeostasis, besides their role of producing insulin. The specific aims are: i) generation of a transgenic model of beta-cell ablation, which will be useful to ii) study beta-cell regeneration and to iii) perform in vivo clonogenic reconstitution assays of transplanted cells. Beyond the basic processes of organ growth and maintenance, this study may have implications for cell replacement therapy in diabetes and for all ethical issues related to the use of embryonic or adult stem cells. Once generated, these transgenic strains will be put into the "public" Beta Cell Biology Consortium (BCBC) mouse repository, so as to become available to the broad scientific community, as we have already done with other transgenic mice that we produced in the past