Paradoxical Effects of NF-kB in Ischemia; Novel Polymeric Gene Silencing in vivo

NF-kB 在缺血中的矛盾作用；

基本信息

批准号：
7882702
负责人：
Walter Keith Jones
金额：
$ 62.77万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7882702
关键词：
Acute Address Adverse effects Affect Basic Science Binding Proteins Binding Sites Biological Candidate Disease Gene Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Death Cell Death Process Cell Survival Cessation of life Chronic Clinical Clinical Data Co-Immunoprecipitations Complex Computer Simulation Coronary Coronary Occlusions DNA DNA Binding DNA delivery Development Dilatation - action Disease Disease Progression Dose Drug or chemical Tissue Distribution Evaluation Functional disorder Future Gadolinium Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Goals Government Heart Heart Diseases Heart failure Hypoxia In Vitro Individual Infarction Injury Interdisciplinary Study Ischemia Knowledge Laboratories Lead Learning Left Left Ventricular Remodeling Link Magnetic Resonance Imaging Measurement Mediating Modeling Molecular Molecular Profiling Morbidity - disease rate Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardium NF-kappa B Necrosis Nucleic Acids Outcome Patients Persons Play Polymers Process Reagent Regulation Reperfusion Injury Reperfusion Therapy Repression Research Role Safety Signal Transduction Small Interfering RNA Stimulus Techniques Technology Testing Therapeutic Therapeutic Effect Therapeutic Uses Transgenic Mice Translations Tweens United States National Institutes of Health Unstable angina Ventricular Function Ventricular Remodeling Viral Work base chromatin immunoprecipitation clinically relevant cytokine efficacy testing implantation in vivo in vivo Model innovation innovative technologies mortality mouse model new technology new therapeutic target novel novel therapeutics pre-clinical preclinical study prevent programs promoter public health relevance response therapeutic target therapy development transcription factor ventricular assist device ventricular hypertrophy viral DNA

项目摘要

DESCRIPTION (provided by applicant): Though the role of genes in heart disease is appreciated, there is currently little understanding of the mechanism by which the transcription factor NF-kB contributes to the antithetical processes of cardioprotection and ischemia/reperfusion (I/R) injury. This Critical Gap In Knowledge prevents the successful development of therapies employing NF-kB inhibition or cytokine blockade in cardiovascular disease. The objective of the proposal is to fill this knowledge gap; to develop a comprehensive understanding of the mechanism by which NF-kB and NF-kB-dependent gene expression networks affect I/R injury, cardioprotection, post-I/R dysfunction and heart failure. We offer the central hypothesis that NF-kB mediates differential responses to different stimuli by regulating distinct sets of NF-kB-dependent genes. We propose three specific aims; 1) Delineate the sets of NF-kB-dependent genes that underlie the antithetical effects of NF-kB upon cell death after I/R and PO, 2) Determine the transcriptional mechanism by which NF-kB modulates gene expression to evoke cell death after I/R and cell survival after PO, 3) Determine the biological effects and therapeutic potential of PGAA polyplexes during acute and chronic post-ischemic disease in vivo. The approach is to employ an hypothesis-driven microarray strategy that takes advantage of our IkBDN mice (block NF-kB) to delineate NF-kB-dependent genes functionally associated with NF-kB-dependent pro-injury and cardioprotective effects. We will also employ an innovative non-viral polymeric nucleic acid delivery technology (PGAA) to block NF-kB activation (decoys) and to silence NF-kB-dependent genes (siRNA) in vivo. We expect that the results will provide a mechanistic understanding of how NF-kB-dependent genes underlie differential responses in the heart. Public Health Relevance: The proposed research is significant because it will lead to identification of new therapeutic targets and development of novel therapies for ischemic heart disease. The proposal develops a novel and innovative set of reagents for basic science that can be used for DNA and siRNA delivery in vivo. The proposal is highly translational in that it develops the therapeutic use of PGAA-mediated decoy and siRNA delivery in pre- clinical studies.

描述（由申请人提供）：尽管基因在心脏病中的作用受到赞赏，但目前对转录因子NF-KB有助于心脏保护和缺血/再灌注（I/R）损伤的机制几乎没有理解。知识的这种关键差距阻止了采用NF-KB抑制作用或心血管疾病中细胞因子封锁的疗法的成功发展。该提案的目的是填补这一知识差距。为了全面了解NF-KB和NF-KB依赖性基因表达网络影响I/R损伤，心脏保护，I/R功能障碍和心力衰竭。我们提供了一个中心假设，即NF-KB通过调节不同的NF-KB依赖性基因来介导对不同刺激的差异反应。我们提出了三个具体目标。 1) Delineate the sets of NF-kB-dependent genes that underlie the antithetical effects of NF-kB upon cell death after I/R and PO, 2) Determine the transcriptional mechanism by which NF-kB modulates gene expression to evoke cell death after I/R and cell survival after PO, 3) Determine the biological effects and therapeutic potential of PGAA polyplexes during acute and chronic post-ischemic disease in体内。该方法是采用一种假设驱动的微阵列策略，该策略利用我们的IKBDN小鼠（块NF-KB）来划定与NF-KB依赖性依赖性亲侵袭性和心脏保护作用相关的NF-KB依赖基因。我们还将采用创新的非病毒聚合物核酸输送技术（PGAA）来阻止NF-KB激活（诱饵），并在体内沉默NF-KB依赖性基因（siRNA）。我们预计结果将对NF-KB依赖性基因的依赖于心脏的差异反应的基础提供一种机械理解。公共卫生相关性：拟议的研究很重要，因为它将导致鉴定出新的治疗靶点和缺血性心脏病的新疗法的发展。该提案开发了一套新颖的基础科学试剂集，可用于体内DNA和siRNA。该提案高度转化，因为它在临床研究中发展了PGAA介导的诱饵和siRNA递送的治疗用途。