Quantitative Analysis of Ethanol-Induced Tissue Injury

乙醇引起的组织损伤的定量分析

基本信息

批准号：
7295936
负责人：
Nikolai Iosifovich Markevich
金额：
$ 12.62万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7295936
关键词：
Accounting Affect Alcohol-Induced Disorders Alcoholism Alcohols Animal Feed Apoptosis Apoptotic Asses BIRC4 gene Behavior Biological Biological Models Biology Caspase Cell Death Cell Membrane Permeability Cells Ceramides Cessation of life Chronic Complement Complex Computer Simulation Computing Methodologies Condition Data Depth Development Disease Educational workshop Electron Transport Equation Equilibrium Ethanol Feedback Generations Goals Hepatocyte Injury Inner mitochondrial membrane Knowledge Laboratories Literature Mediating Mediator of activation protein Membrane Mentors Methods Mitochondria Mitogen-Activated Protein Kinases Modeling Molecular Molecular Biology Molecular and Cellular Biology Outer Mitochondrial Membrane PTEN gene Pathway interactions Permeability Personal Satisfaction Phosphorylation Play Predisposition Probability Process Production Protein Family Proton-Motive Force Reactive Oxygen Species Regulation Research Research Personnel Role Signal Pathway Signal Transduction Simulate Site Solid Specialist Study models Superoxides System Systems Biology Testing Tissues Training Transmembrane Transport Tumor Necrosis Factor-alpha Tumor Necrosis Factors VDAC1 gene Work alcohol abuse therapy alcohol research base career caspase-3 caspase-8 cell injury chronic alcohol ingestion computer generated computerized data processing concept cytokine experience human TNF protein mathematical model pro-apoptotic protein programs response skills

项目摘要

DESCRIPTION (provided by applicant): The career development goal of this proposal is to complement my background in mathematical and computational modeling by receiving training in and gaining experience in the cell and molecular biological aspects of alcohol research, specifically in applications involving cell signaling by reactive oxygen species (ROS)- and tumor necrosis factor (TNF)-a that control cell death and survival. These signaling pathways play key roles in tissue injury and are strongly affected by excessive chronic alcohol consumption. My current skills include development and analysis of mathematical models, systems of ordinary differential equations (ODE), describing complex biological networks and membrane-transport systems with different regulatory loops. I have experience in studying such nonlinear phenomena in ODE as hysteresis, multi-stability and threshold effects as well as auto-oscillations and resonance. In my previous modeling studies of cell signaling networks, I demonstrated the potential for hysteresis, bistability and threshold phenomena in mitogen activated protein kinase (MARK) activation as a result of multi-site (de)phosphorylation in the MARK cascade My entry into the field of the alcohol research will be supervised by my mentor Dr. Jan B. Hoek and my co-mentor Dr. John G. Pastorino, both recognized specialists in alcohol-related cell injury. The training goals of this proposal are a) to obtain more in-depth knowledge of cell and molecular biology, b) to gain experience in current concepts of alcohol-related injury, c) to become familiar with advanced computational methods and experimental approaches that will enable me to conduct quantitative research of apoptosisrelated signaling pathways. This training will consist of taking advanced courses in Cell and Molecular Biology and the biology of alcoholism, and workshops to become familiar with relevant modern experimental approaches. The main research goals of this proposal are to develop quantitative computational models of the control of apoptotic processes that are enhanced by alcohol treatment, resulting in alcohol-induced injury. The research will involve two Specific Aims: 1) To develop a computational model that can provide a quantitative analysis of ethanol-induced alterations in the mitochondria! changes associated with the onset of apoptosis, and 2) To develop a computational model of TNFa-dependent pro- and anti-apoptotic signaling processes that are affected by chronic alcohol treatment, resulting in enhanced susceptibility to cell death.

描述（由申请人提供）：该提案的职业发展目标是通过接受培训并获得酒精研究的细胞和分子生物学方面的经验来补充我在数学和计算建模方面的背景，特别是在涉及电池信号的应用中，氧（ROS）和肿瘤坏死因子（TNF） - 控制细胞死亡和存活。这些信号通路在组织损伤中起关键作用，并受到过度慢性酒精消耗的强烈影响。我目前的技能包括对数学模型的开发和分析，普通微分方程（ODE）的系统，描述具有不同调节循环的复杂生物网络和膜 - 传输系统。我在研究磁滞，多稳定性和阈值效应以及自动振荡和共鸣等ODE中的非线性现象方面有经验。在我先前对细胞信号网络的建模研究中，我证明了由于多站点（DE）磷酸化在Mark级联反应中，有丝分裂原活化蛋白激酶（MARK）激活的滞后性和阈值现象的潜力酒精研究将由我的导师Jan B. Hoek博士和我的同事John G. Pastorino博士进行监督，John G. Pastorino博士都是与酒精有关的细胞损伤专家。该提案的培训目标是a）获得对细胞和分子生物学的更深入的知识，b）获得当前与酒精相关损伤概念的经验，c）熟悉先进的计算方法和实验方法使我能够对凋亡相关的信号通路进行定量研究。该培训将包括参加细胞和分子生物学的先进课程以及酒精中毒的生物学，以及熟悉相关的现代实验方法的研讨会。该提案的主要研究目标是开发用于控制凋亡过程的定量计算模型，这些模型通过酒精治疗增强，从而导致酒精引起的损伤。该研究将涉及两个具体的目的：1）开发一个计算模型，该模型可以对乙醇诱导的线粒体变化进行定量分析！与细胞凋亡的发作相关的变化，以及2）开发受长期饮酒治疗影响的TNFA依赖性促和抗凋亡信号传导过程的计算模型，从而增强了对细胞死亡的易感性。