Exercise-mediated protection against brain metastases

运动介导的脑转移保护

基本信息

批准号：
8712405
负责人：
Michal Toborek
金额：
$ 19.91万
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/8712405
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 Complement Factor B Cytoskeleton Data Development Dextrans Disseminated Malignant Neoplasm Drug Targeting Elements Endothelial Cells Endothelium Equilibrium Etiology Evaluation Event Exercise Exercise Physiology Extravasation Fluorescein-5-isothiocyanate 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 endothelial dysfunction 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，中度至剧烈运动是一种有力的手段降低转移性癌症的发病率。但是，这种有益影响的机制是不完全理解。我们目前的应用专门针对肿瘤的机制细胞渗入大脑。对脑转移的这种强调与我们一致对血脑屏障生理和病理学的兴趣。另外，脑转移是与癌症相关的发病率和死亡率引起的领先原因之一。中心假设本应用的是，运动可以防止血液的发展通过增加抗氧化能力并调节氧化还原 - 毛细管内皮的调节反应。为了研究这一假设，我们将采用一种模仿人类运动的自愿模式的车轮的动物模型。我们将专门针对运动介导的保护针对血管机制的保护肿瘤细胞通过破坏内皮的紧密连接蛋白的渗出。紧的连接是调节脑毛细血管的关键组成部分血脑屏障。从机械上讲，主要重点将放在 RAS和RHO信号传导在磷酸化和紧密连接表达的变化中蛋白质。拟议的研究结合了运动生理学的元素，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。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血脑屏障的关注有关转移，因为肿瘤渗出发生在脑上皮的水平上以及评估体育活动对肿瘤传播和生长。我们认为，从该提案中获得的数据将提供证据，即适度运动可以显着防止血脑转移的发展。此外，对BBB分子和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。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dietary Selenium Supplementation Modulates Growth of Brain Metastatic Tumors and Changes the Expression of Adhesion Molecules in Brain Microvessels.

DOI：
10.1007/s12011-015-0595-x
发表时间：
2016-08
期刊：
Biological trace element research
影响因子：
3.9
作者：
Wrobel JK;Wolff G;Xiao R;Power RF;Toborek M
通讯作者：
Toborek M

Selenoglycoproteins attenuate adhesion of tumor cells to the brain microvascular endothelium via a process involving NF-κB activation.

DOI：
10.1016/j.jnutbio.2014.09.013
发表时间：
2015-02
期刊：
The Journal of nutritional biochemistry
影响因子：
0
作者：
Wrobel JK;Choi JJ;Xiao R;Eum SY;Kwiatkowski S;Wolff G;Spangler L;Power RF;Toborek M
通讯作者：
Toborek M

Diffuse optical monitoring of repeated cerebral ischemia in mice.