High-Resolution Analysis of Juvenile Human Pancreas Maturation

Contact PI: Christopher Wright, D. Phil., Vanderbilt University (UC4 DK108120)

Al Powers, PhD, Investigator, Vanderbilt University
Richard Caprioli, PhD, Investigator, Vanderbilt University
Jeremy Norris, PhD, co-Investigator, Vanderbilt University
Long Cai, PhD, Investigator, California Institute of Technology
Viviana Gradinaru, PhD, Investigator, California Institute of Technology
Marcela Brissova, PhD, co-Investigator, Vanderbilt University

Start Date: September 25, 2015

End Date: May 31, 2020 *


This team brings expertise in pancreas development and physiology, mechanistic studies of the disturbance of pancreas function in diabetes, and also in the development, application and continued optimization of novel methods for high-resolution tissue imaging and single-cell analysis. We will define the normal and dynamic alterations in tissue architecture, cellular-level molecular signatures, and physiological functions, of the human pancreatic islet that occur specifically between 0-5 years of age (the “juvenile period”), which is now emerging as a critical period of development and maturation for this essential organ. While our understanding over this period is limited, new data suggest that the pancreas exhibits a surprising degree of plasticity and maturation in its global tissue architecture, beta-cell physiological function, and the latter’s interplay not only with other hormone-secreting cell types but also the vascular and neural networks. Because very early onset autoimmunity – as measured by antibodies against functional proteins of the human β cell – has been detected within this same juvenile period, it is possible that “cryptic” pancreas/islet defects arising within the juvenile period are a strong driver of future type 1 diabetes (T1D). We hypothesize that these defects within the juvenile period arise because abnormalities in the normal dynamic maturation of islet structure and physiology either improperly engage an imperfectly functioning immune system, or improperly present antigens to a relatively normal immune system, both leading to inadequate tolerance. Many critical aspects of juvenile β-cell development and function (for example, transition from amino-acid- to glucose-responsiveness) are still not known, rooted in a problem of tissue scarcity and because tissues were not prepared in a way conducive for modern analytical approaches. We use advanced tissue-clearing technologies, multiplexed RNA in situ tissue-analysis approaches, and imaging mass spectrometry, and have substantial experience in studying the differentiation and function of human juvenile pancreas. We will be able to apply these novel methods efficiently because we have gained control over the pipeline for tissue procurement and preparation. We will overcome the paucity of information in human tissue about the many developmental regulators that are well known from studies in rodents. Our analyses will provide essential fundamental underpinnings for a structure-function atlas of the human pancreas, especially over the juvenile period, and at the tissue architecture and single-cell level will likely uncover significant findings regarding cellular heterogeneity. We will study key cell-surface, physiological markers, transcription factors, and other markers to define the sequence of events in human juvenile islet development. We also focus on the intra- and inter-islet vascular and neural networks, and the putative role of tissue macrophages. These methods of comprehensive profiling will be applicable to T1D pancreas samples.




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