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Physical Signaling Mechanisms That Regulate Intestinal Architecture

调节肠道结构的物理信号机制

基本信息

批准号：
9885833
负责人：
MICHAEL A PACK
金额：
$ 41.69万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2020-05-19 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9885833
关键词：
Animal Model Animals Architecture Biological Birth Cell membrane Cells Colorectal Cancer Digestive System Disorders Disease Engineering Enteric Nervous System Epithelial Epithelial Cells Epithelium Esophageal Atresia Esophagus Esophagus motility Familial colorectal cancer Family Gastrointestinal Motility Gastrointestinal Neoplasms Gastrointestinal tract structure Genes Germ-Line Mutation Goals Heritability Heterozygote Homozygote Human In Vitro Injury Intestines Knock-in Laboratories Lesion Life Link MYH11 gene Malignant Neoplasms Mammalian Cell Mediating Membrane Modeling Mus Muscle Contraction Mutation Myosin ATPase Myosin Heavy Chains Oncogenic Organ Oxidation-Reduction Oxidative Stress Pathologic Pathway interactions Phenotype Physiology Play Process Proteins Regulation Risk Factors Role Signal Pathway Signal Transduction Small Intestines Smooth Muscle Smooth Muscle Myosins Stomach Stress Syndrome Tissues Translations Variant WNT Signaling Pathway Work Zebrafish cancer cell cell behavior cell motility clinically relevant design experimental study in vivo intestinal epithelium motility disorder mouse model mutant nervous system development novel pup repaired response stressor tissue regeneration tumor progression

项目摘要

PROJECT SUMMARY Physical signals are increasingly recognized as playing an important role in modulating cell behavior. The goal of this proposal is to characterize the cellular response to force-mediated signaling in the intestine and esophagus using zebrafish and mouse models. We have shown that an activating mutation in smooth muscle myosin heavy chain gene myh11 disrupts intestinal architecture in zebrafish meltdown mutants. Physical signals arising from the mutant myosin activate a conserved redox signaling pathway in the intestinal epithelium that drives the formation of plasma membrane protrusions known as invadopodia that degrade matrix proteins. The invadopodia drive the invasive transformation and cystic expansion of the epithelium. Animals that are heterozygous for the meltdown mutation develop normally but are sensitized to form the homozygous cell invasion phenotype when oncogenic signaling pathways activated. The proposal consists of three aims designed to understand how physical signals from unregulated myosin are processed by digestive epithelia and how they may be risk factors for digestive disease. The goal of the first aim are to understand how the mutant smooth muscle myosin initiates invadopodia in the epithelium of meltdown mutants and to compare this to mechanisms that regulate invadopodia formation in mammalian cells. Invadopodia have rarely if ever been observed in vivo, thus this aim offers the opportunity to understand their regulation in a live animal model. The goal of the second aim is to understand how co- activation of KRas and Wnt signaling sensitize heterozygous mutants to invasive triggers. The experiments proposed for this aim have both basic and clinical relevance, as both pathways are activated in human digestive cancers. The goal of the third aim is to characterize a recently engineered mouse model of the meltdown mutation. This includes characterization of esophageal and intestinal phenotypes in homozygous mutants, and comparison with mice newly engineered to carry knock-in mutations that are identical to human MYH11 mutations associated with heritable motility syndromes. Collectively, the proposed experiments will define novel factors and signaling mechanisms that establish and maintain digestive organ architecture and function.

项目总结