Understanding how exocrine-derived signals promote beta cell growth

项目摘要 胰腺通常被认为是两个不同的器官系统，其中内分泌隔室 负责激素分泌，外分泌室负责消化系统的分泌。 内切酶虽然不同，内分泌和外分泌胰腺在功能和结构上是相连的， 共同维持代谢平衡外分泌疾病可影响内分泌; 然而，并非所有外分泌疾病病例都会导致内分泌功能障碍。例如，50 - 80%的 患有胰腺炎或外分泌不足的个体不会发展为糖尿病。这表明，在某些 在某些情况下，外分泌胰腺的丧失可能会支持内分泌的继续生长和功能。 目前，对分子途径和通讯的理解仍然不完全， 存在于胰腺的内分泌和外分泌细胞之间。已发表的研究和我们的初步数据 实验室揭示羟腐胺赖氨酸生物合成在外分泌生长和功能中起作用，这反过来可能影响 β细胞生长羟腐胺赖氨酸的生物合成涉及真核生物翻译的翻译后修饰 起始因子5A（eIF 5A）通过脱氧羟腐胺赖氨酸合酶（DHPS）形成羟腐胺赖氨酸化的eIF 5A （eIF 5AHyp），其在mRNA翻译中起作用。我们的研究表明，eIF 5A在发育中的缺失， 胰腺引起参与外分泌生长和功能的蛋白质合成减少， 外分泌质量的丧失。有趣的是，外分泌量的减少伴随着β细胞的增加， 马萨诸塞州因此，我推测，在细胞外分泌的质量损失，而不是mRNA翻译的改变， 外分泌分化的阶段由于外分泌和外分泌的量减少而驱动β细胞生长。 衍生蛋白质。为了检验这一假设，并确定是否是外分泌的缺失或eIF 5A的缺失， 刺激β细胞扩增，我将在两个具体目标进行实验大纲。aim 1中的实验将 研究外分泌的缺乏如何指导β细胞在胚胎和成人环境中的生长。 目标2中的实验将研究mRNA翻译的改变如何直接影响外分泌生长， 结果，β细胞团。特别是，我的研究可以确定外分泌衍生因子刺激β细胞 增长此外，该奖项将提供关键的全面培训，包括五个中心目标， 包括：1）建立与糖尿病研究相关技术和概念的坚实背景; 2）磨练 我的科学写作技巧交流; 3）练习我的口头科学交流; 4）提高我的 作为导师的技能;以及5）专业职业发展。我的培训计划还包括直接和 我的赞助人和共同赞助人的热情支持，成立了由 NIH资助的研究人员，以及IUPUI生物学系和中心的所有资源/设施 在印第安纳州大学医学院的糖尿病和代谢疾病，这将有助于我的进步 在我成为一个独立的糖尿病研究者的道路上。

PROJECT SUMMARY The pancreas has commonly been considered two distinct organ systems wherein the endocrine compartment is responsible for hormone secretion and the exocrine compartment is responsible for the secretion of digestive enzymes. Although distinct, the endocrine and exocrine pancreas are functionally and structurally connected, working together to maintain metabolic homeostasis. Diseases of the exocrine can impact the endocrine; however, not all cases of exocrine disease result in endocrine dysfunction. For example, 50 - 80% of individuals with pancreatitis or exocrine insufficiency do not develop diabetes. This suggests that in certain instances the loss of exocrine pancreas may support the continued growth and function of the endocrine. Currently, there remains an incomplete understanding of the molecular pathways and communications that exist between cells of the endocrine and exocrine pancreas. Published studies and preliminary data from our lab reveal that hypusine biosynthesis plays a role in exocrine growth and function, which in turn may influence beta cell growth. Hypusine biosynthesis involves the post-translational modification of eukaryotic translation initiation factor 5A (eIF5A) by the enzyme deoxyhypusine synthase (DHPS) to form hypusinated eIF5A (eIF5AHyp), which functions in mRNA translation. Our studies demonstrate that loss of eIF5A in the developing pancreas causes a reduction in the synthesis of proteins involved in exocrine growth and function as well a loss of exocrine mass. Interestingly, the reduction in exocrine mass is concomitant with an increase in beta cell mass. Therefore, I hypothesize that the loss of exocrine mass, rather than altered mRNA translation, at the stage of exocrine differentiation drives beta cell growth due to the reduced amount of exocrine and exocrine- derived proteins. To test this hypothesis and determine if it is the loss of exocrine or the loss of eIF5A that stimulates beta cell expansion, I will perform experiments outline in two specific aims. Experiments in aim 1 will investigate how the absence of exocrine instructs beta cell growth in the embryonic and adult setting. Experiments in aim 2 will investigate how alterations in mRNA translation directly impacts exocrine growth and, resultantly, beta cell mass. In particular, my studies may identify exocrine-derived factors stimulate beta cell growth. Moreover, this award will provide critical holistic training encompassing five central objectives, which include: 1) building a strong background in techniques and concepts pertinent to diabetes research; 2) honing my scientific writing skills communication; 3) practicing my oral scientific communication; 4) enhancing my skills as a mentor; and 5) professional career development. My training plan also includes direct and enthusiastic support from my sponsor and co-sponsor, a thesis advisory committee composed of established NIH-funded investigators, and all of the resources/facilities in the IUPUI Department of Biology and the Center for Diabetes and Metabolic Diseases at the Indiana University School of Medicine, which will help me progress in my path to become an independent, diabetes-focused researcher.