Clinical and Mechanistic Features of Premature Termination Codon Suppression

过早终止密码子抑制的临床和机制特征

基本信息

批准号：
7632078
负责人：
Steven Mark Rowe
金额：
$ 12.78万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2006-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7632078
关键词：
Address Affect Alleles Aminoglycosides Area Arts Attention Binding Bioavailable Biological Availability Biometry Cell physiology Chloride Channels Clinical Clinical Research Clinical Trials Code Collection Commit Complement Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Disease Doctor of Philosophy Dose Drug Kinetics Environment Evaluation Exhibits Future Generations Genetic Gentamicins Hereditary Disease Immunofluorescence Immunologic In Vitro Individual Inherited Instruction Investigation Laboratories Laboratory Study Lead Learning Length Mentors Messenger RNA Metabolism Modality Modeling Multicenter Studies Mutation Names New Agents Nonsense Codon Nonsense-Mediated Decay Nose Nucleotides Operative Surgical Procedures Other Genetics Pathway interactions Pharmaceutical Preparations Physicians Predisposition Process Production Proteins Pulmonology Recombinants Research Research Design Research Personnel Research Project Grants Research Training Resources Role Safety Science Scientist Signal Transduction Structure Terminator Codon Testing Time Toxic effect Training Transcript Translational Research Variant Work career career development cystic fibrosis patients design experience functional restoration human subject improved in vitro activity in vivo interest mRNA Stability novel therapeutics patient population premature programs research clinical testing research facility research study response small molecule success treatment strategy

项目摘要

DESCRIPTION (provided by applicant): CANDIDATE: Steven M. Rowe, MD MSPH is committed to a career in academic pulmonology as a translational scientist focused on cystic fibrosis (CF) and other airways diseases. This proposal is intended to familiarize Dr. Rowe with the design and conduct of leading edge biomedical science in a closely mentored research environment. SPONSORS: Eric Sorscher, MD (Director, UAB CF Research Center) is a national leader in CF research and has extensive experience mentoring physician-scientists. JP Clancy, MD has worked daily with Dr. Rowe in related research projects and will provide instruction regarding the operation of a national multicenter CF clinical trial. George Howard, PhD will direct Dr. Rowe's advanced training in biostatistics. ENVIRONMENT: UAB is well suited to provide translational research training, including state-of-the-art research facilities and excellent career development resources. RESEARCH: CF caused by premature stop mutations results in the production of little or no functional cystic fibrosis transmembrane conductance regulator (CFTR). Certain small molecules have the capacity to reduce the fidelity of nonsense allele recognition, leading to translational readthrough of otherwise truncated CFTR and synthesis of full-length, active protein. This strategy has been successfully employed to correct CFTR function in CF subjects in vivo. A better understanding of mechanisms of action and investigation of more potent agents is required to advance this new treatment strategy. We will study the effects of stop mutation susceptibility to translational readthrough, and evaluate the importance of mRNA stability in this process. PTC124, a new compound that confers very potent stop suppression, will be evaluated in vitro and in a clinical trial. Successful completion of this project will define the potential role of nonsense codon suppression as a future CF therapy. LAY STATEMENT: Correcting premature stop mutations could improve or cure patients with CF and other genetic diseases caused by stop mutations. We propose to study this approach in the laboratory and in a clinical trial using a new, very active compound named PTC124. Results will help determine whether this treatment strategy can be used to treat individuals with CF and other inherited diseases.

描述（由申请人提供）：候选人：MD MSPH的Steven M. Rowe致力于从事学术肺病学职业，是一位专注于囊性纤维化（CF）和其他气道疾病的转化科学家。该建议旨在使Rowe博士在密切指导的研究环境中熟悉领先的生物医学科学的设计和行为。赞助商：医学博士Eric Sorscher（UAB CF研究中心主任）是CF研究的全国领导者，并具有丰富的经验指导医师科学家。 JP Clancy，医学博士每天都与Rowe博士在相关研究项目中工作，并将提供有关国家多中心CF临床试验的运作的指导。乔治·霍华德（George Howard），博士将指导Rowe博士在生物统计学方面的高级培训。环境：UAB非常适合提供转化研究培训，包括最先进的研究设施和出色的职业发展资源。研究：过早停止突变引起的CF导致很少或没有功能性囊性纤维化跨膜电导调节剂（CFTR）产生。某些小分子具有降低废话等位基因识别的保真度的能力，从而导致对原本截短的CFTR的翻译读取和全长活性蛋白的合成。该策略已成功地用于纠正体内CF受试者中的CFTR功能。需要更好地了解动作机制和对更有效药物的调查，以推进这种新的治疗策略。我们将研究停止突变易感性对翻译通读的影响，并评估在此过程中mRNA稳定性的重要性。 PTC124是一种赋予非常有效抑制的新化合物，将在体外和临床试验中进行评估。该项目的成功完成将定义抑制无义密码子作为未来CF疗法的潜在作用。外行陈述：纠正过早停止突变可以改善或治愈CF患者和其他由停止突变引起的遗传疾病。我们建议在实验室和临床试验中使用一种名为PTC124的新化合物研究这种方法。结果将有助于确定该治疗策略是否可以用于治疗CF和其他遗传疾病的人。