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Proteomic and Functional Studies of Mitochondrial Proteins Involved in ROS Metabo

参与 ROS 代谢的线粒体蛋白的蛋白质组学和功能研究

基本信息

批准号：
8050563
负责人：
Yuchun Du
金额：
$ 6.98万
依托单位：
UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
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 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8050563
关键词：
Amino Acids Antineoplastic Agents Apoptosis Apoptotic Biochemical Pathway Biological Biological Process Cancer Patient Cancer cell line Cell Culture Techniques Cell Death Cells Cytosol Diagnosis Event Functional disorder Genetic Goals Induction of Apoptosis Isotopically-Coded Affinity Tagging Malignant Neoplasms Malignant neoplasm of pancreas Mediating Methods Mitochondria Mitochondrial Matrix Mitochondrial Proteins Molecular Organelles Oxidation-Reduction Pancreas Pathway interactions Pharmaceutical Preparations Play Positioning Attribute Production Proteins Proteomics RNA Interference Radiation Radiation therapy Reactive Oxygen Species Resistance Role Screening procedure Signal Pathway Stable Isotope Labeling Survival Rate Techniques Variant base cancer cell cell killing chemotherapy cytochrome c design mitochondrial membrane novel novel therapeutics overexpression pancreatic cancer cells public health relevance response stable isotope

项目摘要

DESCRIPTION (provided by applicant): One of the major factors contributing to the high fatality of pancreatic cancer is the poor response of most pancreatic cancer patients to therapies including radiation therapy and chemotherapy. Our long- term objective of this project is to understand the molecular mechanisms underlying the resistance of pancreatic cancer to therapies. Induction of apoptosis in target cells is a key mechanism by which radiation and chemotherapy induces cell killing. Mitochondrion and mitochondrion-generated reactive oxygen species (ROS) play essential roles in the cell death pathways. In the mitochondria dependent apoptotic pathways, after the release of the apoptotic factors, such as cytochrome c, the downstream biochemical pathways appear to be shared by different cells. We hypothesize that the mitochondrial proteins involved in ROS production or scavenging, which determine the ROS levels in mitochondria, may be responsible for the resistance of pancreatic cells to therapies. Accordingly, we propose to use quantitative proteomic methods to systematically screen mitochondrial proteins that are involved in ROS production and scavenging in pancreatic cancer cells with different sensitivity to ROS inducing drugs (Specific Aim 1). After the proteomic screening, RNAi or overexpression techniques will be used to manipulate the expression of the identified target proteins in cells, and the effects of the altered expression of the target proteins on cellular ROS accumulation, and cellular apoptosis will be determined (Specific Aim 2). Identifications of the protein factors that are closely associated with the resistance of pancreatic cancer cells to anti-cancer drugs may provide valuable information for designing new novel therapeutic strategies to overcome the resistance of pancreatic cancer to therapies. PUBLIC HEALTH RELEVANCE: The objective of this project is to identify novel protein targets that may be responsible for chemo- resistance of pancreatic cancer. Novel quantitative proteomic methods will be used to systemically compare mitochondrial redox proteins in chemo-sensitive and chemo-resistant pancreatic cancer cells. Molecular and cell biological techniques will be used to assess the biological functions of the identified target proteins.

描述（由申请人提供）：导致胰腺癌高死亡率的主要因素之一是大多数胰腺癌患者对包括放射治疗和化学治疗在内的治疗的反应较差。我们这个项目的长期目标是了解胰腺癌对治疗耐药的分子机制。诱导靶细胞凋亡是放疗和化疗诱导细胞杀伤的关键机制。线粒体和线粒体产生的活性氧（ROS）在细胞死亡途径中起重要作用。在线粒体依赖的凋亡途径中，在释放凋亡因子（例如细胞色素c）之后，下游生化途径似乎由不同细胞共享。我们假设参与ROS产生或清除的线粒体蛋白质（其决定线粒体中的ROS水平）可能是胰腺细胞对治疗的抗性的原因。因此，我们建议使用定量蛋白质组学方法来系统地筛选参与胰腺癌细胞中ROS产生和清除的线粒体蛋白，这些细胞对ROS诱导药物具有不同的敏感性（特异性目的1）。在蛋白质组学筛选后，将使用RNAi或过表达技术来操纵细胞中鉴定的靶蛋白的表达，并将确定靶蛋白的改变表达对细胞ROS积累和细胞凋亡的影响（具体目标2）。确定与胰腺癌细胞对抗癌药物的耐药性密切相关的蛋白质因子可能为设计新的治疗策略以克服胰腺癌对治疗的耐药性提供有价值的信息。公共卫生相关性：该项目的目的是鉴定可能导致胰腺癌化疗耐药的新蛋白质靶点。新的定量蛋白质组学方法将用于系统地比较化学敏感和化学耐药胰腺癌细胞中的线粒体氧化还原蛋白。分子和细胞生物学技术将用于评估所鉴定的靶蛋白的生物学功能。