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Regional and lobular heterogeneity of human pancreas morphology and function in type 1 diabetes pathogenesis

1型糖尿病发病机制中人胰腺形态和功能的区域和小叶异质性

基本信息

批准号：
10223289
负责人：
MARK A. ATKINSON
金额：
$ 42.17万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-24 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223289
关键词：
3-Dimensional Acinar Cell Acinus organ component Address Affect Amylases Area Atrophic Autoantibodies Autoimmunity Beta Cell Biological Assay Blood Vessels Body Weight decreased Body mass index C-Peptide Cell Communication Cell physiology Cells Cellular biology Cessation of life Characteristics Data Development Diabetes Mellitus Diabetes autoantibodies Diabetes prevention Digestion Disease Elements Endocrine Environment Enzymes Event Exocrine pancreas Extracellular Matrix Functional disorder Gene Expression Glucagon Head Health Heterogeneity Histologic Hormones Human Immune In Situ Individual Infiltration Inflammatory Response Insulin Insulin-Dependent Diabetes Mellitus Investigation Islet Cell Islets of Langerhans Knowledge Lipase Lobular Lobule Location Measures Mechanics Mediating Modification Molecular Morphology Mus Neurons Organ Organ Donor Organ Weight Output Pancreas Pathogenesis Pathogenicity Pathologic Pattern Persons Physiology Positioning Attribute Predisposition Procedures Process Regulation Resistance Resources Role Serum Signal Transduction Slice Sorting - Cell Movement Stimulus Structure Structure of beta Cell of islet Tail Techniques Technology Testing Three-dimensional analysis Tissue Donors Tissue Slice Technology Tissues Trypsinogen Tumor-infiltrating immune cells Variant Vascularization Weight autoimmune pathogenesis blood glucose regulation cellular imaging density diabetes pathogenesis experience imaging study improved insulitis islet lymphatic vessel morphometry nerve supply new therapeutic target non-diabetic novel peripheral blood preservation prevent programs regional difference response sex trait two-dimensional

项目摘要

Through programs such as the Network for Pancreatic Organ donors with Diabetes (nPOD), highly valuable tissues from persons with various stages and durations of type 1 diabetes (T1D) are now available. As a result, our collective knowledge of the pathogenic events underlying T1D development has improved substantially. However, studies simultaneously assessing functional and morphological traits of the human pancreas have not been performed, limiting our understanding of the processes governing organ physiology in health versus pathophysiology in T1D. Despite being in important research resource, investigations of isolated islets are confounded by the isolation procedure, which induces an inflammatory response, morphological modifications, and altered gene expression. Furthermore, the isolation procedure relies on the structural integrity of the islets to withstand the enzymatic and mechanical sorting process. Most importantly, separation of islets from their surrounding tissue removes any influence and information regarding the local adjacent elements, which could be of importance, especially in pathological settings. We believe the characterization of islets as well as exocrine tissues (function, regulation, and cellular interactions) and their roles in the pathogenesis of T1D would be improved through studies of viable human pancreatic tissue containing intact islets and acini. We propose to utilize the extremely novel pancreas tissue slice technology to substantially expand our knowledge of endocrine and exocrine function and their interaction in normal (i.e., control) and T1D pancreas tissues obtained through the nPOD program. This technology, originally established by Dr. Speier (mPD/PI, HMGU), produces “slices” of fresh pancreatic tissue with minimal mechanical damage and without enzymatic digestion; enabling in situ investigations of islet cell biology in a relatively unperturbed tissue setting. Following functional stimulation assays for endocrine (insulin and glucagon) and exocrine secretion (amylase, lipase, trypsinogen) as well as dynamic imaging studies of cellular signaling (Ca2+ flux), slices will be fixed and analyzed by 3D morphometry. Amongst the many questions that will be addressed, we seek to improve our understanding on the functional implications of the lobular and regional (i.e., head, body or tail) heterogeneous pancreatic morphology, including islet density, size and cellular composition, exocrine enzyme expression and distribution, as well as vascular and neuronal density. Furthermore, we aim to address its role in the distinct lobular and regional pathological progression of T1D (i.e., insulitis, β-cell dysfunction and destruction, loss of acinar cell/organ mass). Thus, we pose to test the hypothesis that the disparate organ weight loss as well as the lobular heterogeneity of insulitis and β-cell destruction within the human T1D pancreas is the result of inter-regional and intra-lobular differences in endocrine and exocrine pancreas morphology and function. Our objective is to correlate islet and exocrine physiology and pathophysiology to their location within the pancreas and to cellular characteristics of the surrounding microenvironment; efforts that should impact attempts at T1D prevention/reversal.

通过糖尿病胰腺器官捐献网络（nPOD）等项目，非常有价值