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 型糖尿病的原因尚不清楚，那么主要是因为人类胰岛及其 糖尿病研究界现在尚未研究与免疫系统的相互作用。 考虑到在糖尿病啮齿动物模型中获得的结果与人类状况缺乏相关性。 响应，有一个新的一致努力来获取和研究相关材料，即人类 该研究计划的长期目标是了解胰腺在健康和疾病中的作用。 以及在糖尿病状态进展过程中人类胰岛发生的生理变化。 该应用的目的是确定内分泌、血管和免疫区室如何成熟 并在胰岛出生后发育过程中进行功能相互作用，我们将重点关注幼体的成熟。 因为这是一个早期出现的自身免疫与自身免疫密切相关的阶段。 总体假设是β细胞定向的发病。 自身免疫与胰岛细胞分子表型的发育改变有因果关系 我们认为成熟过程使胰岛容易发生炎症。 并促进自身免疫的发展。拟议研究的基本原理是理解。 是什么让小岛变得脆弱，不仅有助于解释它的衰落，而且还为干预提供线索 因此，该项目与 NIH 的使命相关，并且响应研究目标。 NIDDK 题为“人类高分辨率探索”的资助机会公告 在初步数据的指导下，我们将通过三个具体的研究来检验我们的假设。 目的：(1) 确定胰岛内分泌细胞功能成熟的机制，(2) 确定如何 建立血管功能的内分泌控制，并且（3）确定表型和 胰岛驻留巨噬细胞的行为在第一个目标下，我们将研究大量的结构和功能。 β 和 α 细胞充分发挥分泌潜力所需的变化，我们将记录在这三个目标中。 通过功能成像进行细胞反应并测量供体活体胰腺切片中的激素释放 这些研究将得到对 0 至 10 岁细胞的 scRNA-seq 分析的补充。 在第二个目标下，我们将确定内分泌细胞如何建立对胰岛的控制。 血管周细胞，胰岛血流的主要调节者，在第三个目标下，我们将研究如何调节血管周细胞。 胰岛驻留巨噬细胞的表型和功能在胰岛成熟过程中发生变化。 拟议的研究意义重大，因为预期结果可能揭示发育过程 削弱胰岛的自然防御并引发局部免疫细胞的异常反应。 流程对于提出旨在预防 1 型糖尿病发展的干预目标至关重要。