TRANSGENIC MODEL OF INDUCIBLE DIABETES

描述（由申请人提供）： 我们提出了快速诱导型糖尿病转基因模型的产生。该提案的主要目的是确定成年小鼠中产生胰岛素的β细胞的来源。在这些动物中，在发育期间、出生后生长期间或成年动物中，在给予诱导药物后，将诱导胰腺β细胞的完全或部分选择性破坏。这些动物将不会被工程化以研究I型糖尿病的发病机制和自身免疫机制，也不会发生炎症;相反，它们将有助于准确评估成年胰腺在再生过程中的胰岛（β细胞）新形成，该再生过程应遵循诱导剂治疗。它们还将用于重建测定，以确定注射的干/祖细胞的分化潜力，无论是静脉注射还是直接注射到胰腺中，来源于胰腺或胰腺外组织（例如，G.肝、神经或造血干细胞，或ES细胞克隆）。顺便说一句，这种转基因模型将代表一个独特的工具，研究参与胰腺稳态的β细胞，除了他们的作用，产生胰岛素。具体目标是：i）产生β-细胞消融的转基因模型，其将用于ii）研究β-细胞再生和iii）进行移植细胞的体内克隆发生重建测定。除了器官生长和维持的基本过程之外，这项研究可能对糖尿病的细胞替代疗法以及与使用胚胎或成体干细胞相关的所有伦理问题都有影响。一旦产生，这些转基因品系将被放入“公共”β细胞生物学联盟（BCBC）小鼠库，以便广泛的科学界可以使用，就像我们过去生产的其他转基因小鼠一样

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