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 胰岛是维持血糖稳态所必需的功能性微器官。 胰岛中产生胰岛素的β细胞的损失或功能障碍导致血糖水平的失调， 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-细胞质量和功能扩展的途径。胰岛不是孤立存在的， 神经支配在胰岛发育中的作用以及在健康和疾病中的功能是一个新兴的重要领域。 胰岛由交感神经以及副交感神经密集地支配，尽管 在较小的程度上。神经元输入对于控制成年胰岛的激素释放和维持血糖是必要的 体内平衡以前，我们的实验室表明，胰岛在发育过程中的交感神经支配是 对于小鼠中建立胰岛结构和功能成熟至关重要。最近的研究结果表明， 胰岛神经支配在糖尿病动物模型和人体组织中经历了实质性的结构变化。 总之，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 以及生理和病理条件下的激素分泌。 妊娠是一个独特的生理条件，此时胰岛显示出惊人的形态和功能 在成年生活中的可塑性。为了响应增加的代谢需求，成人β细胞动态响应， 促进增殖和分泌功能。然而，潜在的分子机制， 妊娠期间胰岛的结构和功能可塑性在很大程度上仍不清楚。根据我初步的 结果，该项目的总体目标是测试神经支配有助于胰岛可塑性的假设， 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验证这一假设。 使用整体包埋免疫染色、3D成像和神经消融研究的神经和内分泌胰腺 在妊娠和对照小鼠中。全器官成像将保留内分泌系统之间的空间关系， 胰岛和邻近神经。通过对胰岛神经进行基因消融，我将解决 神经对妊娠小鼠胰岛结构和功能适应性变化的贡献。 通过这个奖学金申请，我将定义一个新的监管途径，具体来说， 外周神经，在胰岛和β细胞适应高代谢需求的条件下。我也会 发展必要的实验，沟通和领导技能，以实现我成为 独立调查员我的培训将通过严格的研究计划，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。