Mechanistic studies on the regeneration of β-cells to balance the diabetic metabolic state in pancreas of LEW.1AR1-iddm rat and comparative in humans

β 细胞再生平衡 LEW.1AR1-iddm 大鼠胰腺糖尿病代谢状态的机制研究与人类比较

• 批准号: 455203589
• 负责人: Professorin Dr. Anne Jörns
• 金额: --
• 依托单位: Institut für Klinische Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/455203589?language=en
• 关键词: Mechanistic; studies; regeneration; cells; balance

By combining a T cell antibody with antibodies against proinflammatory cytokines, especially against TNFα, a therapy concept for curing type 1 diabetes in a rat model (IDDM rat) of human type 1 diabetes was established for the first time. The rats treated in this way became normoglycaemic again. The aim of this subsequent application is to clarify the underlying pathways of β-cell regeneration in the endocrine pancreas. Differentiated β-cells enter the mitotic division via various factors and thus normalize the β-cell mass by increasing the proliferation and inhibiting apoptosis. DNA repair mechanisms also contribute to regeneration by converting damaged β-cells into intact ones. In addition to replication, new β-cells can also be formed from other pancreatic cell types via various pancreatic and β-cell specific transcription factors and proliferation factors via neogenesis. The subsequent process of functional maturation of the β-cells is mediated by known (flattop) markers and newly discovered makers by microarray analysis. The regeneration markers are examined using a variety of methods at the gene and protein level. The results are collected in the rat model in non-diabetic, acutely diabetic and successfully treated pancreata compared to human, non-diabetic and diabetic pancreata of different forms. These new findings on β-cell regeneration are intended to clarify the mechanisms on which the new successful therapeutic approaches for curing type 1 diabetes are based.

通过将T细胞抗体与抗促炎细胞因子、特别是抗TNFα的抗体相结合，首次建立了在人类1型糖尿病大鼠模型（IDDM大鼠）中治愈1型糖尿病的治疗概念。以这种方式治疗的大鼠的血糖再次恢复正常。随后应用的目的是阐明内分泌胰腺中 β 细胞再生的潜在途径。分化的β细胞通过多种因素进入有丝分裂，从而通过增加增殖和抑制凋亡来使β细胞质量正常化。 DNA 修复机制还通过将受损的 β 细胞转化为完整的细胞来促进再生。除了复制之外，新的β细胞还可以通过各种胰腺和β细胞特异性转录因子和增殖因子通过新生从其他胰腺细胞类型形成。 β 细胞功能成熟的后续过程是由已知（平顶）标记和通过微阵列分析新发现的标记介导的。使用多种方法在基因和蛋白质水平上检查再生标记。结果是在非糖尿病、急性糖尿病和成功治疗的大鼠模型中收集的，与不同形式的人类、非糖尿病和糖尿病胰腺进行比较。这些关于 β 细胞再生的新发现旨在阐明治疗 1 型糖尿病的新成功治疗方法所依据的机制。