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: 10251144
• 负责人: Marcela Brissova
• 金额: $ 63.23万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251144
• 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.

如果尚不清楚1型糖尿病的原因，主要是因为人类胰岛及其 与免疫系统的相互作用尚未研究。糖尿病研究社区现在即将到来 与糖尿病啮齿动物模型中获得的人类所获得的人类状况相关。在 回应，有一项新的协同努力来获取和研究相关材料，即人类 胰腺，健康和疾病。该研究计划的长期目标是了解解剖学 在人类胰岛向糖尿病状态的过程中发生的身体变化。 该应用的目的是确定内分泌，血管和免疫室如何成熟 并在胰岛的产后发展期间功能相互作用。我们将专注于少年的成熟 时期是因为这是一个阶段，在此期间自身免疫与 倾向于公开1型糖尿病。总体假设是β细胞导向的发作 自身免疫有时与胰岛细胞的分子表型的发育改变有关，并与 胰岛架构的变化。我们建议成熟过程使胰岛容易受到炎症 并支持自身免疫的发展。拟议研究的理由是理解 使小马脆弱的原因不仅有助于解释其垮台，而且还提供了干预的线索 策略。因此，该项目与NIH的使命相关，并且对研究目标有回应 NIDDK的资金机会公告，题为“人类的高分辨率探索 伊斯特组织环境”。在初步数据的指导下，我们将通过追求三个特定的特定来检验我们的假设 目的：（1）确定胰岛内分泌细胞功能成熟的机制，（2）确定如何 建立了对血管功能的内分泌控制，（3）确定表型的变化和 胰岛居民巨噬细胞的行为。在第一个目标下，我们将研究庞大的结构和功能 Beta和Alpha细胞所需的变化才能达到其全部分泌潜力。在这三个目标中，我们将记录 通过功能成像和测量激素释放的细胞反应，从供体的活胰腺切片中释放 年龄0至10岁。这些研究将通过对从中分类的细胞进行SCRNA-SEQ分析来完成 孤立的胰岛。在第二个目标下，我们将确定内分泌细胞如何建立对 血管周细胞，胰岛中血流的主要调节剂。在第三个目标下，我们将研究 胰岛质量巨噬细胞的表型和功能在胰岛成熟期间变化。 拟议的研究很重要，因为预期的结果可以揭示发展过程 减少了胰岛的自然防御能力，并触发了局部免疫细胞的异常反应。知道这些 过程对于旨在防止1型糖尿病发展的建议干预目标至关重要。