Project Abstracts - HPAC

Stephen Speier, PhD, Investigator, Paul Langerhans Institute Dresden
Marcela Brissova, PhD, Investigator, Vanderbilt University

Start Date: September 25, 2018
Start Date: June 30, 2022

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Abstract

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.

Meet the Grant Team 

Investigators

Alejandro Caicedo, PhD University of Miami

Stephen Speier, PhD Paul Langerhans Institute Dresden

Marcela Brissova, PhD Vanderbilt University

 

Publications

• Genetic risk converges on regulatory networks mediating early type 2 diabetes
• Human Pseudoislet System for Synchronous Assessment of Fluorescent Biosensor Dynamics and Hormone Secretory Profiles
• A bright future for glucagon and alpha cell biology
• A Defect in Mitochondrial Complex III but Not in Complexes I or IV Causes Early β-Cell Dysfunction and Hyperglycemia in Mice
• Protocol to generate and utilize pancreatic tissue slices to study endocrine and exocrine physiology in situ from mouse and human tissue
• Immunotherapy With Low-Dose IL-2/CD25 Prevents β-Cell Dysfunction and Dysglycemia in Prediabetic NOD Mice
• The human α cell in health and disease
• Human pancreatic capillaries and nerve fibers persist in type 1 diabetes despite beta cell loss
• Restoring glutamate receptor signaling in pancreatic alpha cells rescues glucagon responses in type 1 diabetes
• RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes
• Targeting the Pancreatic α-Cell to Prevent Hypoglycemia in Type 1 Diabetes
• Microvessels enhance vascularization and function of transplanted insulin-producing cells
• Integrated Analysis of the Pancreas and Islets Reveals Unexpected Findings in Human Male With Type 1 Diabetes
• Combinatorial transcription factor profiles predict mature and functional human islet α and β cells
• Optical Imaging of Pancreatic Innervation
• The Human Islet: Mini-organ with Mega-impact
• Deciphering the Complex Communication Networks That Orchestrate Pancreatic Islet Function
• Pancreatic Beta Cells Communicate With Vagal Sensory Neurons
• Beta cell dysfunction in diabetes: the islet microenvironment as an unusual suspect
• Pancreatlas: Applying an Adaptable Framework to Map the Human Pancreas in Health and Disease
• Blood Flow in the Pancreatic Islet: Not so Isolated Anymore
• Integrated human pseudoislet system and microfluidic platform demonstrates differences in G-protein-coupled-receptor signaling in islet cells
• Pancreas tissue slices from organ donors enable in situ analysis of type 1 diabetes pathogenesis
• Secretory Functions of Macrophages in the Human Pancreatic Islet are Regulated by Endogenous Purinergic Signaling
• A Nervous Breakdown that May Stop Autoimmune Diabetes
• The Local Paracrine Actions of the Pancreatic Alpha Cell