In situ analysis of functional endocrine, vascular, and immune cell interactions during early postnatal development of the human pancreas

人类胰腺出生后早期发育过程中功能性内分泌、血管和免疫细胞相互作用的原位分析

• 批准号: 9789864
• 负责人: Marcela Brissova
• 金额: $ 63.81万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789864
• 关键词: 10 year old; 3-Dimensional; Adolescent; Adult; Alpha Cell; Anatomy; Architecture; Autoimmunity; Behavior; Beta Cell; Biology; Birth; Blood Vessels; Blood flow; Cell Communication; Cell Maturation; Cells; Communities; Complement; Data; Development; Developmental Process; Diabetes Mellitus; Disease; Ecosystem; Effector Cell; Endocrine; Environment; Event; Functional Imaging; Funding Opportunities; Goals; Health; Homeostasis; Hormone secretion; Hormones; Human; Immune; Immune response; Immune system; In Situ; Infiltration; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Intervention; Islet Cell; Islets of Langerhans; Lead; Leukocytes; Life; Measurement; Measures; Mission; Molecular; Molecular Profiling; Morphology; National Institute of Diabetes and Digestive and Kidney Diseases; Neurons; Pancreas; Paracrine Communication; Pathogenesis; Pericytes; Phenotype; Physiological; Pilot Projects; Positioning Attribute; Predisposition; Process; Production; Regulation; Research; Resolution; Rodent; Rodent Model; Signal Pathway; Signal Transduction; Signaling Molecule; Slice; Somatostatin; Structure; Techniques; Testing; Time; Tissues; United States National Institutes of Health; Work; aged; cell type; diabetic; endocrine pancreas development; extracellular; human model; innovation; insulin secretion; islet; macrophage; molecular phenotype; pancreas development; pancreatic juice; paracrine; postnatal; postnatal development; preservation; prevent; programs; recruit; response; single-cell RNA sequencing; tripolyphosphate

If the causes of type 1 diabetes are not known it is mainly because the human pancreatic islet and its interactions with the immune system have not been studied. The diabetes research community is now coming to terms with the lack of relevance to the human situation of results obtained in rodent models of diabetes. In response, there is a new concerted effort at obtaining and studying the relevant material, namely the human pancreas, in health and disease. The long-term goal of this research program is to understand the anatomical and physiological changes that occur in the human islet during the progression towards the diabetic state. The objective of this application is to determine how the endocrine, vascular and immune compartments mature and interact functionally during the postnatal development of the islet. We will focus on the juvenile maturation period because it is a stage during which early-arising autoimmunity is strongly correlated with the predisposition towards overt type 1 diabetes. The overarching hypothesis is that the onset of beta cell-directed autoimmunity is causally related to developmental alterations in the molecular phenotypes of islet cells and to changes in islet architecture. We propose that maturation processes make islets susceptible to inflammation and facilitate the development of autoimmunity. The rationale for the proposed research is that understanding what makes the islet vulnerable will not only help explain its downfall but also provide clues for intervention strategies. This project is thus relevant to the mission of the NIH and is responsive to the research objectives of the Funding Opportunity Announcement from the NIDDK entitled “High-Resolution Exploration of the Human Islet Tissue Environment”. Guided by preliminary data, we will test our hypothesis by pursuing three specific aims: (1) determine the mechanisms of functional maturation of islet endocrine cells, (2) determine how endocrine control of vascular function is established, and (3) determine changes in the phenotype and behavior of islet resident macrophages. Under the first aim, we will study the massive structural and functional changes needed for beta and alpha cells to reach their full secretory potential. In all three aims, we will record cellular responses with functional imaging and measure hormone release in living pancreas slices from donors aged 0 to 10 years old. These studies will be complemented by scRNA-seq analyses of cells sorted from isolated islets. Under the second aim, we will determine how the endocrine cells establish control of the vascular pericyte, the major regulator of blood flow in the islet. Under the third aim, we will examine how the phenotype and function of the islet resident macrophages changes during the maturation of the islet. The proposed research is significant because the anticipated results could reveal developmental processes that diminish the islet’s natural defenses and trigger abnormal responses from local immune cells. Knowing these processes is crucial to propose intervention targets aimed at preventing the development of type 1 diabetes.

如果1型糖尿病的病因尚不清楚，那主要是因为人类胰岛和它的