Antagonistic Pleiotropy in JNK signaling: dissecting age-dependent interactions

JNK 信号传导中的拮抗多效性：剖析年龄依赖性相互作用

• 批准号: 1355240
• 负责人: Michael Shapira
• 金额: $ 92.74万
• 依托单位: University of California-Berkeley
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1355240&HistoricalAwards=false
• 关键词: Antagonistic; Pleiotropy; JNK; signaling; dissecting

The theory of Antagonistic Pleiotropy postulates that aging is a consequence of inverse correlation between age and selection pressure. Under this theory, positive selection of mechanisms with early-life beneficial effects occurs, in spite of late-life detrimental effects. Understanding when and how such mechanisms become detrimental is crucial for understanding the principles directing the evolution of aging and the aging process itself. However, our understanding of the molecular underpinnings of antagonistic pleiotropy is lacking. This award will support investigation of a novel mechanism involving the conserved C. elegans JNK protein homolog KGB-I to provide relevant information about the molecular mechanisms of antagonistic pleiotropy and aging. KGB-1 provides protection against heavy metals and protein folding stress during development but reverses its contribution and becomes detrimental during early adulthood, sensitizing animals to stress and shortening their lifespan. The project seeks to understand what causes the switch in KGB-1's effect and the general implications of the switch for aging. The project aims will be achieved by dissecting, genetically and biochemically, age-dependent interactions of KGB-1. Specific studies will be conducted to: 1) Characterize age-dependent and tissue-specific interactions between KGB-1 and other proteins; 2) Examine contribution of genes induced in a KGB-1-, and age-dependent manner to downstream phenotypes; 3) Identify proteins physically interacting with KGB-1 in different ages to characterize shifts in KGB-1's network of interactions. Mutant, RNAi knock-down animals, or transgenic strains will be used in these studies to examine genetic and physical interactions between KGB-1 and its mediators. Additional strains will be used to characterize tissue specificity in the contribution of KGB-1 to stress-resistance phenotypes and in its interactions with its mediators. The research will provide information on a fundamental feature of the evolution of aging and provide a better understanding of the aging process itself. Undergraduate and graduate students, including individuals from underrepresented groups, will be trained in scientific research, participate in research and scientific meetings, and publish their results during the project. In addition, science enrichment outreach to local elementary schools will be conducted. All microarray data generated as part of the study will be uploaded upon publication to the Gene Expression Omnibus (GEO: http://www.ncbi.nlm.nih.gov/geo/) database repository. Molecular biology reagents (i.e. plasmids, bacterial clones) generated as part of this work will be available to members of the scientific community upon request. Transgenic C. elegans strains generated by this project will be available immediately after publication to members of the scientific community and will be deposited in the C. elegans Genetics Center at the University of Minnesota (http://www.cgc.cbs.umn.edu/) for wider distribution. Results will be published in peer-reviewed journals, preferably open access ones, and presented at research conferences.

拮抗性多效性理论假设衰老是年龄和选择压力之间的反相关性的结果。在这一理论下，尽管有后期有害影响，但具有早期生命有益作用的机制的积极选择仍会发生。了解这种机制何时以及如何有害对于理解指导衰老演变和衰老过程本身的原理至关重要。 然而，我们缺乏对拮抗性多效性分子基础的理解。该奖项将支持对涉及保守的秀丽隐杆线虫JNK蛋白质同源性kgb-i的新机制的研究，以提供有关拮抗性多效性和衰老的分子机制的相关信息。 KGB-1在发育过程中提供了防御重金属和蛋白质折叠应力的保护，但逆转了其贡献，并在成年初期变得有害，使动物敏感并缩短其寿命。该项目试图了解是什么原因导致KGB-1效果的转换以及转换对衰老的一般影响。该项目的目的将通过在遗传和生化，KGB-1的年龄相互作用上解剖来实现。具体研究将进行：1）表征KGB-1与其他蛋白质之间的年龄依赖性和组织特异性相互作用； 2）检查以KGB-1-诱导的基因的贡献，以及年龄依赖性对下游表型的贡献； 3）在不同年龄识别与KGB-1物理相互作用的蛋白质，以表征KGB-1相互作用网络中的变化。这些研究将使用突变体，RNAi敲除动物或转基因菌株检查KGB-1及其介体之间的遗传和物理相互作用。额外的菌株将用于表征KGB-1对应激表型及其与介体相互作用的贡献中的组织特异性。 该研究将提供有关衰老演变的基本特征的信息，并更好地了解衰老过程本身。 本科生和研究生，包括来自代表性不足的团体的个人，将接受科学研究，参加研究和科学会议的培训，并在项目期间发布结果。此外，还将对当地小学进行科学丰富的宣传。 作为研究一部分生成的所有微阵列数据将在出版时上传到基因表达综合（GEO：http：//www.ncbi.nlm.nih.gov/geo/）数据库存储库。分子生物学试剂（即质粒，细菌克隆）作为这项工作的一部分产生，可应要求提供给科学界的成员。 该项目产生的转基因秀丽隐杆线虫菌株将在出版给科学界成员后立即提供，并将存放在明尼苏达大学的C.秀丽隐杆遗传学中心（http://www.cgc.cbs.umn.edu/），以进行更广泛的分布。结果将在经过同行评审的期刊上发布，最好是开放访问权限，并在研究会议上介绍。