Role of AKT in Beta Cell Apoptosis

I型糖尿病是一种以胰岛内胰腺β细胞的自身免疫性破坏为特征的疾病。虽然许多工作已经进入异常的内部定向免疫应答的特征的描绘，但相当少的注意力被导向理解β细胞杀伤的机制和开发策略以积极影响体内新β细胞的生长。尽管如此，大量证据表明β细胞内细胞凋亡率的升高显著促进了疾病的进展。细胞凋亡是一种程序性细胞死亡的形式，其在进化过程中一直被保存，通过典型的形态学和生物化学特征被识别，并且对生物体控制发育、重塑和衰老的能力很重要。许多质膜和细胞内成分已被证明可以调节细胞凋亡。近年来，丝氨酸/苏氨酸蛋白激酶Akt/PKB受到了广泛关注，它是一个信号级联反应的中心，可以有效地拮抗细胞凋亡。此外，Akt/PKB还参与细胞生长、细胞周期和合成代谢的调节。目前的建议旨在确定依赖性信号通路在β细胞中发挥积极的调节作用，以防止细胞凋亡，增加细胞生长，并可能增强葡萄糖与胰岛素分泌的偶联。增强β细胞的存活、分泌效率和增殖的激素，如胰岛素和IGF-1，是许多细胞类型中Akt-PKB的有效激活剂，与上述假设一致。通过同源重组的方法建立Akt/PKB基因缺陷小鼠。将研究来自这些动物的胰岛的胰岛素分泌、生长和耐受许多促凋亡刺激（包括自身免疫攻击）的能力。这些实验可能会更清楚地了解导致β细胞破坏性生长的途径，并提出预防策略。

Type I diabetes mellitus is a disease characterized by autoimmune destruction of pancreatic beta cells within the Islets of Langerhans. Though much work has gone into a delineation of the characteristic of the abnormal, internally directed immune response, considerably less attention has been directed towards understanding the mechanism of beta cell killing and developing strategies to positively influence the growth of new beta cells in vivo. Nonetheless, substantial evidence suggests than an elevated rate of apoptosis within the beta cell contributes significantly the progression of the disease. Apoptosis is a form of programmed cell death that has been conserved through evolution, is recognized by typical morphological and biochemical features, and is important to the organism's ability to control development, remodeling and aging. A number of plasma membrane and intracellular components have been shown to regulate apoptosis. Recently, much attention has been focused on the serine/threonine protein kinase Akt/PKB, which is central to a signaling cascade that potently antagonizes apoptosis. Moreover, Akt/PKB has been implicated in regulation of cell growth, cell cycle, and anabolic metabolism. The current proposal aims to determine the dependent signaling pathways exert a positive regulatory effect in the beta cell to prevent apoptosis, increase cellular growth, and possibly enhance the coupling of glucose to insulin secretion. Hormones, such as insulin and IGF-1, which enhance the survival, secretory efficiency, and proliferation of beta cells, are effective activators of Akt-PKB in numerous cell types, consistent with the above hypothesis. The transgenic mice and to create mice deficient in Akt/PKB by virtue of homologous recombination. Islets from these animals will be studied in regard to insulin secretion, growth, and the ability to withstand a number of pro- apoptotic stimuli, including autoimmune attack. It is likely these experiments will provide a clearer understanding of the pathways that lead to destruction growth of beta cells and suggest strategies for its prevention.