Endothelial Dysfunction in Intestinal Radiation Toxicity

肠道辐射毒性中的内皮功能障碍

基本信息

批准号：
7225494
负责人：
Martin Hauer-Jensen
金额：
$ 28.61万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-07-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7225494
关键词：
Abbreviations Abdomen Acute Address Affect Alteplase Ancrod Animal Model Anti-Inflammatory Agents Anti-inflammatory Anticoagulants Apoptotic Avidin Biotin Blood Clot Blood Vessels Blood coagulation Cell Death Cell Surface Receptors Cell physiology Cholesterol Chronic Class Clinical Coagulants Coagulation Process Complex Condition Cyclic AMP Cytidine Monophosphate Data Deposition Development Disadvantaged Dose Dose-Limiting Endothelial Cells Epithelial Event Extravasation F2R gene Fibrin Fibrinogen Fibrosis Foundations Functional disorder Future Grant Hirudin Hirudins In Vitro Inflammation Inflammatory Injury Intercellular Adhesion Molecules Interleukin-1 Interleukin-4 Intervention Intestinal Fibrosis Intestines Laboratories Lead Link Lipids Localized Lung Malignant Neoplasms Mediator of activation protein Methods Modeling Molecular Mucositis Mus Nitric Oxide Normal tissue morphology Organ Outcome PAR-1 Receptor Pathogenesis Pathway interactions Pharmaceutical Preparations Plasma Plasminogen Inactivators Play Principal Investigator Protein C Proteinase-Activated Receptors Proteins Radiation Radiation Injuries Radiation Pneumonitis Radiation Toxicity Radiation therapy Rattus Recombinants Relative (related person)Research Research Personnel Research Project Grants Risk Role Safety Sclerosis Score Small Intestines Superoxide Dismutase Testing Thrombin Thrombin Receptor Thrombomodulin Time Toxic effect Transforming Growth Factors Tumor Necrosis Factor-alpha Tumor Necrosis Factors Uncertainty Up-Regulation Vascular Permeabilities Week Wild Type Mouse Work activated Protein C base clinically relevant connective tissue growth factor extracellular human NOS3 protein human TNF protein in vivo inhibitor/antagonist insight intercellular cell adhesion molecule interstitial irradiation laser capture microdissection lomustine/methotrexate/procarbazine protocol novel pre-clinical preclinical study programs research study response

项目摘要

DESCRIPTION (provided by applicant): Abdominal radiation therapy is often dose-limited by the risk of intestinal toxicity (radiation enteropathy). Radiation enteropathy is characterized by epithelial barrier breakdown and mucosal inflammation, and subsequent development of progressive fibrosis and vascular sclerosis. Microvascular injury is believed to promote radiation enteropathy development, but molecular links have not yet been established in vivo. Clinical and preclinical studies performed by the PI strongly suggest that radiation-induced endothelial dysfunction, notably loss of vascular thromboresistance due to deficient thrombomodulin (TM) expression, is mechanistically involved in radiation enteropathy development. TM is an endothelial cell protein that modulates thrombin's functions, and essentially converts thrombin from a pro-coagulant to an anticoagulant. After irradiation, deficient levels of TM lead to increased formation of thrombin. Thrombin, in addition to its key role in coagulation, also regulates inflammation and fibrosis. This research project uses validated, genetically modified animal models and pharmacologic compounds, along with quantitative molecular methods, to systematically examine, in vivo, a) the relative significance of thrombin's various effects in context of the intestinal radiation response, and b) endothelial-directed interventions aimed at ameliorating radiation enteropathy. Specifically, the project will 1) examine whether fibrin deposition adversely affects intestinal radiation fibrosis; 2) investigate whether blocking the cellular thrombin receptor, proteinase-activated receptor 1, ameliorates radiation enteropathy; 3) assess whether exogenous administration of activated protein C, an anticoagulant and anti-inflammatory mediator that is activated by thrombin in the presence of TM, influences the intestinal radiation response; 4) test whether statins, a commonly used class of cholesterol-lowering drugs with vasculoprotective effects, ameliorate chronic intestinal radiation fibrosis; and 5) determine whether the enteroprotective effect of statins requires upregulation of TM. These studies will provide substantial new insight into the basic pathogenesis of the intestinal radiation response. A comprehensive understanding of these underlying mechanisms is critical for identifying clinically relevant targets for intervention. This project may thus facilitate development of specific strategies to minimize intestinal radiation toxicity, thereby making radiation therapy safer and more effective.

描述（由申请人提供）：腹部辐射疗法通常受到肠道毒性的风险（辐射肠病）的限制。辐射肠病的特征是上皮屏障崩溃和粘膜炎症，以及随后进行性纤维化和血管硬化症的发展。据信微血管损伤可以促进辐射肠病的发育，但尚未在体内建立分子联系。 PI进行的临床和临床前研究强烈表明，辐射诱导的内皮功能障碍，特别是由于缺乏血小板蛋白（TM）表达而导致的血管血栓抗性丧失，机械上与辐射肠肠疗法发育有关。 TM是一种调节凝血酶功能的内皮细胞蛋白，基本上将凝血酶从促凝剂转化为抗凝剂。辐照后，缺乏TM水平会导致凝血酶的形成增加。凝血酶除了在凝结中的关键作用外还调节炎症和纤维化。该研究项目使用经过验证的，转基因的动物模型和药理学化合物以及定量的分子方法，系统地检查体内a）凝血酶在肠道辐射反应中的各种效应的相对重要性，以及b）内皮导向的干预措施，旨在放射辐射辐射肠道疗法。具体而言，该项目将1）检查纤维蛋白沉积是否不利影响肠道纤维化； 2）研究阻断细胞凝血酶受体，蛋白酶激活的受体1是否可以改善辐射肠病； 3）评估活化蛋白C的外源给药是在TM存在下通过凝血酶激活的抗凝剂和抗炎介质是否会影响肠辐射反应； 4）测试他汀类药物是否是一种常用的降低胆固醇的药物，具有血管保护作用，可以改善慢性肠辐射纤维化； 5）确定他汀类药物的肠化保护作用是否需要上调TM。这些研究将为肠道辐射反应的基本发病机理提供大量的新见解。对这些基本机制的全面理解对于确定临床相关的干预目标至关重要。因此，该项目可能有助于开发特定策略，以最大程度地减少肠道辐射毒性，从而使辐射疗法更安全，更有效。