Exercise-mediated protection against brain metastases

运动介导的脑转移保护

基本信息

批准号：
7985358
负责人：
Michal Toborek
金额：
$ 30.81万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7985358
关键词：
Abbreviations Actins Address Animal Model Animals Antioxidants Attenuated Biological Models Biology Blood Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Brain Neoplasms C57BL/6 Mouse Cancer Etiology Caveolae Caveolins Cell Surface Receptors Cerebrum Clinical Cytoskeleton Data Development Dextrans Disseminated Malignant Neoplasm Drug Delivery Systems Elements Endothelial Cells Endothelium Equilibrium Etiology Evaluation Event Exercise Exercise Physiology Extravasation Functional disorder Future GTP-Binding Proteins Glutathione Goals Growth Human In Situ Incidence Injection of therapeutic agent Integral Membrane Protein Intercellular Junctions Internal carotid artery structure Label Lewis Lung Carcinoma Link Malignant Epithelial Cell Malignant Neoplasms Manganese Superoxide Dismutase Mediating Membrane Membrane Microdomains Metastatic malignant neoplasm to brain Modeling Moderate Exercise Molecular Monomeric GTP-Binding Proteins Morbidity - disease rate Mus Neoplasm Metastasis Nuclear Oxidases Oxidation-Reduction Oxidative Stress Pathology Pathway interactions Pattern Permeability Phosphorylation Physical activity Physiology Process Property Proteins Proteomics Regulation Research Rodent Role Running Signal Pathway Signal Transduction Solid Staining method Stains Systems Biology Techniques Therapeutic Tight Junctions Tissues Very Light Exercise advanced system base brain tissue capillary caveolin 1 dextran in vivo Model interest junctional adhesion molecule mitochondrial dysfunction mortality neoplastic cell novel occludin oxidation prevent protective effect protein expression public health relevance research study response rho sedentary tissue processing tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Clinical evidence indicates that moderate to vigorous exercise is a powerful means to reduce metastatic cancer incidence. However, the mechanisms of this beneficial influence are not fully understood. Our present application is specially focused on the mechanisms of tumor cell extravasation into the brain. Such an emphasis on brain metastases is consistent with our interest in the blood-brain barrier physiology and pathology. In addition, brain metastases are one of the leadings causes of cancer-related morbidity and mortality. The central hypothesis of the present application is that exercise protects against the development of blood- borne brain metastases by increasing antioxidant capacity and modulating redox- regulated responses in the capillary endothelium. To study this hypothesis, we will employ an animal model of wheel running mice that mimics the voluntary pattern of human exercise. We will specifically focus on the exercise-mediated protection against vascular mechanisms of tumor cell extravasation via disruption of tight junction proteins of the endothelium. Tight junctions are the critical components of the brain capillaries which regulate the integrity of the blood-brain barrier. Mechanistically, the main emphasis will be placed on the involvement of the Ras and Rho signaling in alterations of phosphorylation and expression of tight junction proteins. The proposed research combines elements of exercise physiology, clinical approaches (namely, tumor dissemination and growth), cancer progression, and molecular and vascular biology. In addition, we will employ advanced systems biology approaches. Novelty and significance of the present proposal are related to our focus on the blood-brain barrier in brain metastasis, as tumor extravasation occurs at the level of the cerebrovasculature endothelium and the evaluation of the protective effects of physical activity on tumor dissemination and growth. We believe that the data obtained from this proposal will provide evidence that even moderate exercise can significantly protect against the development of blood-brain metastases. Furthermore, a better understanding of the pathophysiological regulation of BBB molecular and functional properties is critical in assessing brain metastasis etiology and in identifying future drug targets to develop more effective therapeutic approaches. PUBLIC HEALTH RELEVANCE: We propose that exercise can attenuate the formation of brain tumor metastases at the level of the blood-brain barrier (BBB) via antioxidant related mechanisms. Specifically, we will explore the link between exercise and the protection against disruption of tight junction proteins, alterations of caveolae-associated redox signaling, and transcapillary dissemination of tumor cells. We believe that the data obtained from this proposal will provide evidence that exercise can significantly protect against the development of blood-brain metastases.

描述（由申请人提供）：临床证据表明，适度至剧烈的运动是降低转移性癌症发病率的有力手段。然而，这种有益影响的机制尚未完全了解。我们目前的应用特别关注肿瘤细胞外渗到大脑中的机制。对脑转移的重视与我们对血脑屏障生理学和病理学的兴趣是一致的。此外，脑转移是癌症相关发病率和死亡率的主要原因之一。本申请的中心假设是运动通过增加抗氧化能力和调节毛细血管内皮中的氧化还原调节反应来防止血源性脑转移的发展。为了研究这一假设，我们将采用轮跑小鼠的动物模型来模仿人类锻炼的自愿模式。我们将特别关注运动介导的通过破坏内皮紧密连接蛋白来防止肿瘤细胞外渗的血管机制。紧密连接是脑毛细血管的关键组成部分，可调节血脑屏障的完整性。从机制上讲，重点将放在 Ras 和 Rho 信号传导参与磷酸化和紧密连接蛋白表达的改变上。拟议的研究结合了运动生理学、临床方法（即肿瘤传播和生长）、癌症进展以及分子和血管生物学的要素。此外，我们将采用先进的系统生物学方法。本提案的新颖性和意义与我们对脑转移中血脑屏障的关注有关，因为肿瘤外渗发生在脑血管内皮水平，以及评估体力活动对肿瘤扩散和生长的保护作用。我们相信，从该提案中获得的数据将提供证据，证明即使是适度的运动也可以显着预防血脑转移的发生。此外，更好地了解 BBB 分子和功能特性的病理生理调节对于评估脑转移病因和确定未来药物靶点以开发更有效的治疗方法至关重要。公共健康相关性：我们认为运动可以通过抗氧化相关机制减弱血脑屏障（BBB）水平的脑肿瘤转移的形成。具体来说，我们将探讨运动与防止紧密连接蛋白破坏、小凹相关氧化还原信号传导改变以及肿瘤细胞经毛细血管传播之间的联系。我们相信，从该提案中获得的数据将提供证据证明运动可以显着预防血脑转移的发生。