Role of Sympathetic Innervation in Islet Plasticity during Pregnancy.

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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.