Role of Sympathetic Innervation in Islet Plasticity during Pregnancy.

交感神经支配在怀孕期间胰岛可塑性中的作用。

• 批准号: 10388837
• 负责人: Joselyn Stibalis Yamamoto
• 金额: $ 4.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-16 至 2025-02-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388837
• 关键词: 3-Dimensional; Ablation; Address; Adult; Affect; Anatomy; Animal Model; Architecture; Area; Beta Cell; Biological Assay; Blood Glucose; Blood Vessels; Cardiovascular Diseases; Cell Proliferation; Cells; Choline O-Acetyltransferase; Chronic Disease; Communication; Development; Diabetes Mellitus; Diabetes prevention; Disease; Endocrine; Fellowship; Functional disorder; Genetic; Goals; Health; Health Care Costs; Hormone secretion; Hormones; Human; Image; Impairment; Injury; Instruction; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Laboratories; Leadership; Life; Maintenance; Mentors; Metabolic; Molecular; Morphology; Mus; Nerve; Nerve Growth Factors; Neuronal Plasticity; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Optics; Organ; PDGFRB gene; Pancreas; Pathologic; Pathway interactions; Pericytes; Peripheral; Peripheral Nerves; Physiological; Pregnancy; Quality of life; Regulatory Pathway; Research; Research Personnel; Resources; Retinal Diseases; Role; Secretory Cell; Signal Transduction; Structure; Testing; Three-Dimensional Imaging; Training; Tyrosine 3-Monooxygenase; Universities; acetylcholine transporter; autonomic nerve; base; blood glucose regulation; cholinergic; defined contribution; density; endocrine pancreas development; experimental study; functional plasticity; glucose tolerance; human tissue; improved; insight; insulin secretion; insulin sensitivity; islet; nerve supply; neurotrophic factor; pregnant; preservation; prevent; response; skills; spatial relationship

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.

项目摘要 Langerhans的胰岛是功能性微孔，对于葡萄糖稳态至关重要。 胰岛中产生胰岛素β细胞的丧失或功能障碍导致血糖水平和血糖水平失调 导致糖尿病。预防糖尿病和治疗的重要目标是更好地理解 管理β细胞质量和功能扩展的途径。胰岛并非孤立地存在，一个 新兴重要的领域是神经在胰岛发展和健康和疾病中的作用中的作用。 胰岛通过交感神经以及副交感神经密集地支配，尽管 在较小程度上。神经元输入对于控制成年胰岛中的激素释放并维持葡萄糖是必需的 稳态。以前，我们的实验室表明，发展过程中胰岛的同情神经是 对于建立小鼠的胰岛结构和功能成熟至关重要。最近的发现表明 胰岛神经在糖尿病和人体组织的动物模型中经历了实质性的结构变化。 这些研究共同强调了研究神经对胰岛形态的贡献的迫切需要 生理和病理状况中的激素分泌。 当胰岛显示出惊人的形态和功能时，怀孕是一种独特的生理状况 成人生活中的可塑性。响应代谢需求的增加，成年β细胞动态地做出了反应 增强扩散及其分泌功能。但是，分子机制 怀孕期间胰岛的结构和功能可塑性在很大程度上仍然不清楚。根据我的初步 结果，该项目的总体目标是检验以下假设，即神经在 怀孕。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，使用全置免疫染色，3D成像和神经消融研究 在怀孕和控制小鼠中。全器成像将保留内分泌之间的空间关系 胰岛和邻近神经。通过进行胰岛神经的遗传消融，我将解决必需品 神经对怀孕小鼠胰岛结构和功能自适应变化的贡献。 通过此奖学金申请，我将定义一个新的监管途径，特别是 在高代谢需求的情况下，胰岛和β细胞适应性的周围神经。我也会 发展实现我的目标所必需的实验，沟通和领导能力 独立研究者。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可用的出色培训资源和设施 通过约翰·霍普金斯大学。