Role of Sympathetic Innervation in Islet Plasticity during Pregnancy.

项目摘要 朗格汉斯人的胰岛是维持血糖稳态必不可少的功能微器官。 胰岛中产生胰岛素的β细胞丢失或功能障碍会导致血糖水平的失调和 会导致糖尿病。糖尿病预防和治疗的一个重要目标是更好地了解 控制β细胞质量和功能扩张的途径。胰岛并不是孤立存在的，而且 新出现的重要领域是神经在胰岛发育中的作用以及在健康和疾病中的功能。 胰岛密集地由交感神经和副交感神经支配，尽管 在较小的程度上。神经元输入是控制成人胰岛激素释放和维持血糖所必需的 动态平衡。此前，我们的实验室表明，发育过程中胰岛的交感神经支配是 对于建立小鼠的胰岛结构和功能成熟是必不可少的。最近的研究结果表明， 在糖尿病动物模型和人体组织中，胰岛神经支配经历了实质性的结构变化。 总而言之，这些研究强调了研究神经支配对胰岛形态的贡献的迫切需要。 生理和病理条件下的激素分泌。 怀孕是一种独特的生理状态，当胰岛表现出惊人的形态和功能时 成人生活中的可塑性。作为对增加的新陈代谢需求的反应，成年β细胞通过 增强细胞增殖和分泌功能。然而，潜在的分子机制 怀孕期间胰岛的结构和功能可塑性仍然很大程度上不清楚。根据我的初步调查 结果：本项目的总体目标是验证神经支配有助于胰岛可塑性的假设。 怀孕了。我将通过定义自主神经之间的解剖和功能相互作用来检验这一假设 神经和内分泌胰腺的整体免疫染色、3D成像和神经消融研究 在怀孕小鼠和对照小鼠身上。全器官成像将保留内分泌之间的空间关系 胰岛和邻近神经。通过对胰岛神经进行基因消融，我将解决 神经在妊娠小鼠胰岛结构和功能适应性改变中的作用。 通过这次奖学金申请，我将定义一条新的监管途径，具体地说， 周围神经，在高代谢需求条件下的胰岛和β细胞适应。我也会 培养必要的实验、沟通和领导技能，以实现我成为 一名独立调查员。我的培训将得到严格的研究计划、专业知识和 我的导师和论文委员会的指导，以及优秀的培训资源和设施 通过约翰·霍普金斯大学。

Project Summary Pancreatic islets of Langerhans are functional micro-organs that are essential for glucose homeostasis. Loss or dysfunction of insulin-producing beta-cells in islets results in dysregulation of blood glucose levels and leads to diabetes. An important goal in diabetes prevention and treatment is a better understanding of the pathways governing expansion of beta-cell mass and function. Pancreatic islets do not exist in isolation, and an area of emerging importance is the role of innervation in islet development and functions in health and disease. Pancreatic islets are densely innervated by sympathetic nerves, as well as by parasympathetic nerves, although to a lesser extent. Neuronal input is necessary to control hormone release in adult islets and maintain glucose homeostasis. Previously, our laboratory showed that sympathetic innervation of islets during development is essential for establishing islet architecture and for functional maturation in mice. Recent findings indicate that islet innervation undergoes substantial structural changes in animal models of diabetes and in human tissues. Together, these studies highlight a critical need to investigate the contribution of innervation to islet morphology and hormone secretion in physiological and pathological conditions. Pregnancy is a unique physiological condition when islets show striking morphological and functional plasticity in adult life. In response to increased metabolic demand, adult beta-cells dynamically respond by enhancing proliferation and their secretory function. However, the molecular mechanisms underlying the structural and functional plasticity of islets during pregnancy remain largely unclear. Based on my preliminary results, the overall goal of this project is to test the hypothesis that innervation contributes to islet plasticity during pregnancy. I will test this hypothesis by defining anatomical and functional interactions between autonomic nerves and the endocrine pancreas using whole-mount immunostaining, 3D imaging, and nerve ablation studies in pregnant and control mice. Whole-organ imaging will preserve the spatial relationships between endocrine islets and neighboring nerves. By performing genetic ablation of islet nerves, I will address the essential contribution of nerves to adaptive changes in islet structure and function in pregnant mice. Through this fellowship application, I will define a new regulatory pathway, specifically, the role of peripheral nerves, in islet and beta-cell adaptation during a condition of high metabolic demand. I will also develop the experimental, communication, and leadership skills necessary to accomplish my goal of becoming an independent investigator. My training will be facilitated by the rigorous research plan, the expertise and guidance of my mentor and thesis committee, and the outstanding training resources and facilities available through Johns Hopkins University.