Molecular Pathogenesis of Radiation Enteropathy

描述（由申请人提供）：尽管放射治疗的计划和交付取得了进展，但腹部肿瘤的治疗往往受到肠道毒性（放射性肠病）风险的剂量限制。放射性肠病的特点是上皮屏障破坏、粘膜炎症和进行性纤维化。以前认为放射性肠病完全是隐窝细胞死亡的结果的观点已被取代。相反，现在人们普遍认识到，许多功能性和继发性改变有助于放射性肠病的病理生理表现。这些变化是旨在预防和/或减少辐射引起的肠道毒性的干预措施的有希望的目标。在肠道中，神经系统和免疫系统细胞之间有着重要的联系。值得注意的是，肠粘膜的感觉神经和常驻肥大细胞构成了一个功能单元，通过双向相互作用调节许多生理和病理过程。我们最近证明肠感觉神经和肥大细胞之间的串扰在很大程度上调节了放射性肠病的发展。拟议的研究将使用经过验证的遗传和药理学方法，结合定量结构终点和分子方法，系统地剖析这些神经免疫相互作用调节肠道辐射反应的机制。该项目将1)研究降钙素基因相关肽（CGRP）在感觉神经和肥大细胞之间的串扰中的作用；2)确定凝血酶在多大程度上调节肠感觉神经的保护特性；3)评估内皮素（ET）系统在肥大细胞调节放射性肠病发生机制中的作用；最后4)研究蛋白酶激活受体2 （PAR2）在辐射诱导的肠道炎症和/或纤维化中的作用，PAR2是一种由肥大细胞蛋白酶激活的受体。这些实验基于之前资助期间产生的数据，将为肠道辐射反应的基本发病机制提供实质性的新见解。推进对放射性肠病基本机制的理解对于确定干预目标至关重要。因此，这项研究将有助于制定具体的策略，以尽量减少肠道辐射毒性，从而使放射治疗更安全，更有效。这个研究项目的重点是对癌症幸存者来说很重要的问题，特别是如何使放射治疗更安全、更有效。公共卫生相关性：这个特定项目的总体目标是研究肠道免疫系统和神经系统之间的相互作用如何影响辐射损伤的发展。这些研究将对肠道辐射损伤发生的机制产生新的见解，并有助于制定减少这种损伤的策略。

DESCRIPTION (provided by applicant): Despite progress in planning and delivery of radiation therapy, treatment of abdominal tumors is often dose-limited by the risk of intestinal toxicity (radiation enteropathy). Radiation enteropathy is characterized by epithelial barrier breakdown, mucosal inflammation, and progressive fibrosis. The previous notion that radiation enteropathy develops exclusively as a result of crypt cell death has been supplanted. Instead, it is now widely recognized that many functional and secondary changes contribute to the pathophysiological manifestations of radiation enteropathy. These changes are promising targets for interventions aimed at preventing and/or reducing radiation-induced bowel toxicity. In the intestine, there are important connections between the nervous system and cells of the immune system. Notably, sensory nerves and resident mast cells in the bowel mucosa constitute a functional unit that regulates many physiological and pathological processes through bidirectional interactions. We recently demonstrated that crosstalk between intestinal sensory nerves and mast cells substantially regulate the development of radiation enteropathy. The proposed research will use validated genetic and pharmacologic approaches, coupled with quantitative structural endpoints and molecular methods, to systematically dissect the mechanisms by which these neuroimmune interactions modulate the intestinal radiation response. The project will 1) examine the role of calcitonin gene-related peptide (CGRP) in the crosstalk between sensory nerves and mast cells; 2) determine to what extent thrombin regulates the protective properties of enteric sensory nerves; 3) assess the role of the endothelin (ET) system in the mechanisms by which mast cells regulate radiation enteropathy development; and finally 4) investigate the role of proteinase activated receptor 2 (PAR2), a receptor that is activated by mast cell proteinases, in radiation-induced intestinal inflammation and/or fibrosis. These experiments are based on data generated during the previous funding period and will provide substantial new insight into the basic pathogenesis of the intestinal radiation response. Advancing the understanding of the basic mechanisms underlying radiation enteropathy is critical for identifying targets for intervention. This research will thus facilitate development of specific strategies to minimize intestinal radiation toxicity in the clinic and thereby make radiation therapy safer and more effective. This research program is focused on issues that are important to cancer survivors, specifically on how to make radiation therapy safer and more effective. PUBLIC HEALTH RELEVANCE: The overall goal of this specific project is to investigate how interactions between the immune system and nervous system in the intestine affect the development of radiation injury. These studies will generate new insight into the mechanisms by which intestinal radiation injury occurs and help develop strategies to minimize such injury.