Exercise-mediated protection against brain metastases

运动介导的脑转移保护

基本信息

批准号：
8548093
负责人：
Michal Toborek
金额：
$ 5.18万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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/8548093
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 Targeting Elements Endothelial Cells Endothelium Equilibrium Etiology Evaluation Event Exercise Exercise Physiology Extravasation Fluorescein-5-isothiocyanate 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 research study response rho sedentary tissue processing tumor tumor progression zonula occludens-1 protein

项目摘要

ABSTRACT 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.

抽象的临床证据表明，适度到剧烈的运动是一种有效的手段降低转移性癌症的发生率。然而，这种有益影响的机制是没有完全理解。我们目前的应用特别关注肿瘤的机制细胞外渗到大脑中。这种对脑转移的重视与我们的观点是一致的。对血脑屏障生理学和病理学感兴趣。此外，脑转移是癌症相关发病率和死亡率的主要原因之一。中心假设本申请的目的是运动可以防止血液的发展通过增加抗氧化能力和调节氧化还原来预防脑转移毛细血管内皮的调节反应。为了研究这个假设，我们将采用一种模拟人类运动自愿模式的轮式小鼠动物模型。我们将特别关注运动介导的血管机制的保护肿瘤细胞通过破坏内皮紧密连接蛋白而外渗。紧的连接点是脑毛细血管的关键组成部分，可调节脑部毛细血管的完整性血脑屏障。从机制上看，主要强调的是主体的参与。 Ras 和 Rho 信号传导改变磷酸化和紧密连接的表达蛋白质。拟议的研究结合了运动生理学、临床方法的要素（即肿瘤扩散和生长）、癌症进展以及分子和血管生物学。此外，我们将采用先进的系统生物学方法。新奇和本提案的意义与我们对大脑中血脑屏障的关注有关转移，因为肿瘤外渗发生在脑血管内皮水平以及体力活动对肿瘤扩散的保护作用评估生长。我们相信，从该提案中获得的数据将提供证据，即使适度的运动可以显着预防血脑转移的发生。此外，更好地了解 BBB 分子和病理生理学调节功能特性对于评估脑转移病因和确定未来至关重要药物靶标以开发更有效的治疗方法。