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Interplay Between SERPINB1 and TLR2/TLR4 in Beta Cell Regeneration

SERPINB1 和 TLR2/TLR4 在 Beta 细胞再生中的相互作用

基本信息

批准号：
10378332
负责人：
ROHIT N. KULKARNI
金额：
$ 20.53万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-15 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378332
关键词：
Adult B Cell Proliferation Beta Cell Blood Vessels CDKN2A gene Cell Cycle Cellular Metabolic Process Data Diabetes Mellitus Diet Disease Equilibrium Etiology Genetic Homeostasis Human Immune Immune signaling Individual Innate Immune System Insulin Insulin Resistance Knockout Mice Laboratories Ligands Liver MEKs Mediating Metabolic Michigan Modeling Molecular Mus Natural Immunity Natural regeneration Nature Nuclear Organism Overnutrition Patients Peripheral Pharmacology Qi Recombinants Regenerative capacity Regulation Reporting Signal Pathway Signal Transduction Stimulus Structure of beta Cell of islet System TLR2 gene TLR4 gene Testing Therapeutic Time Universities Work age related aged beta cell replacement cell injury cell regeneration cell replacement therapy diabetes mellitus therapy diabetic patient diabetogenic diet-induced obesity efficacy testing emerging adult glycemic control health application infancy innovation insight islet mouse model new therapeutic target novel response restoration translational study

项目摘要

SUMMARY Pancreatic β cell regeneration is a promising approach for the treatment of insulin dependent type-1 (T1D) and -2 diabetes (T2D). However, the nature of the signaling pathway(s) responsible for the age-dependent decline of β cell proliferation remains an enigma, a significant roadblock in diabetes therapy. The Kulkarni laboratory at Joslin Diabetes Center recently reported that SerpinB1 secreted from the liver promotes β cell proliferation (El Ouaamari et al. Cell Metabolism 2016) while the Qi laboratory at the University of Michigan showed that Toll- Like Receptors 2 and 4 (TLR2/TLR4) signaling pathways, two redundant innate immune signaling pathways, block diet-induced β cell replication (Nat Immunol, under revision). In this application, the Kulkarni and Qi laboratories will team up to test an overarching hypothesis that the antagonistic interplay between SerpinB1 and TLR2/TLR4 maintains a balance in favor of β cell regeneration in both mice and humans under diabetogenic stimuli. We propose that TLR2/TLR4 activation in diet-induced obesity blocks SerpinB1-mediated β cell replication while simultaneous disruption of TLR2/TLR4 signaling pathways on β cells may promote β cell proliferation via SerpinB1-dependent manner. To this end, we will (i) perform lineage tracing to test the hypothesis that TLR2/TLR4 regulates β cell replication in a β cell autonomous manner; (ii) delineate the interplay between TLR2/TLR4 and SerpinB1 and the underlying mechanism in the regulation of β cell regeneration; and (iii) determine the therapeutic potential of targeting TLR2/TLR4 and SerpinB1 in β cell proliferation and regeneration using human β cells and islets. Hence, this study will be instrumental in demonstrating that metabolic and innate immune systems, two primitive systems critical for the long-term homeostasis of multi-cellular organisms, have evolved to promote cooperative, adaptive responses against diverse environmental challenges such as overnutrition. If successful, this study will help realize therapeutic potential of our discoveries and benefit millions of diabetic patients worldwide by delivering novel, invaluable therapeutics for the treatment of widespread diabetes. RELEVANCE TO HUMAN HEALTH: This application, with parallel mouse models and human islets studies, will reveal novel molecular and cellular mechanisms, shaped by metabolic and innate immunity signaling pathways, which govern β cell replication and metabolic homeostasis. Hence, this study may fundamentally change our views of metabolic-innate immune interactions, and hold tremendous promise to uncover both novel disease mechanisms and pharmacological targets aimed at treating and reversing the underlying metabolic imbalances in diabetes.

总结