Role of AKT in Beta Cell Apoptosis

1型糖尿病是一种以朗格汉斯胰岛内胰岛细胞自身免疫破坏为特征的疾病。尽管对异常的内部定向免疫反应的特征进行了大量的研究，但对β细胞杀伤机制的理解和制定积极影响体内新β细胞生长的策略的关注却相当少。尽管如此，大量证据表明，β细胞凋亡率升高对疾病的进展起着重要作用。细胞凋亡是一种程序性细胞死亡的形式，在进化过程中被保存下来，具有典型的形态和生化特征，对生物体控制发育、重塑和衰老的能力至关重要。许多质膜和细胞内成分已被证明可以调节细胞凋亡。最近，丝氨酸/苏氨酸蛋白激酶Akt/PKB备受关注，它是信号级联的核心，可有效拮抗细胞凋亡。此外，Akt/PKB还参与细胞生长、细胞周期和合成代谢的调控。本研究旨在确定依赖信号通路在β细胞中发挥积极的调节作用，以防止细胞凋亡，促进细胞生长，并可能增强葡萄糖与胰岛素分泌的偶联。胰岛素和IGF-1等激素可以提高β细胞的存活、分泌效率和增殖，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，构建Akt/PKB缺失小鼠。这些动物的胰岛将被研究胰岛素分泌、生长和抵抗一些促凋亡刺激的能力，包括自身免疫攻击。这些实验很可能会让我们更清楚地了解导致β细胞破坏生长的途径，并提出预防的策略。

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.