Mechanisms of the Response to Hydrogen Sulfide

描述(申请人提供)：所有有机体必须在不断变化的环境条件下保持动态平衡才能生存。不幸的是，与衰老相关的生理变化降低了维持体内平衡的能力，增加了对疾病、损伤和感染的易感性。硫化氢(H_2S)是由动物细胞自然产生的，可以延长线虫的寿命和耐热性。这项提议与我的长期目标有关，我的长期目标是领导一个独立的研究小组，旨在了解动物体内硫化氢效应的机制基础。该奖项提供的培训将使我能够发展实验室管理技能，发表研究成果，并开始寻找独立的职位。此外，该研究计划将帮助我发展使用细胞学和遗传学技术的重要技能，这些技术对于充分利用线虫系统的力量至关重要。在第一个目标中，我将测试假设，即硫化氢延迟线虫年龄相关的变化。这些实验将确定硫化氢如何影响不同组织类型中的不同生物过程。在第二个目标中，我将确定与硫化氢反应有关的基因和途径。我将描述表达硫化氢诱导表型的突变的特征，并确定哪些突变与SIR-2.1一起影响寿命。在一种补充方法中，我将评估在基于RNAi的筛查中确定的基因的作用，这些基因与SIR-2.1一样，是硫化氢诱导的变化所必需的。最后，我将使用微阵列方法来确定受硫化氢诱导的变化影响的因素，这些因素与寿命延长相关。这些实验将揭示硫化氢影响寿命的分子机制(S)。马克·罗斯博士的实验室是我职业发展的极好培训环境，这要归功于过去成功地使用细胞生物学和遗传分析来了解线虫的生物学过程。此外，罗斯实验室已经证明，硫化氢对哺乳动物的生理有深远的影响，可以提高在不断变化的条件下的存活率。相关性：在无脊椎动物模型中，通过研究影响寿命的因素，已经确定了许多保守的衰老过程。这项研究计划旨在确定硫化氢延长线虫寿命的机制。这些研究可能有助于解释导致与年龄相关的生理衰退的过程，这些过程降低了在不断波动的环境中生存的能力，这导致了与衰老相关的死亡率增加。

DESCRIPTION (provided by applicant): All organisms must maintain homeostasis in the face of changing environmental conditions to survive. Unfortunately, physiological changes associated with aging decrease the capacity to maintain homeostasis, increasing susceptibility to disease, injury and infection. Hydrogen sulfide (H2S), which is naturally produced by animal cells, increases lifespan and thermotolerance in C. elegans. This proposal is related to my long- term goal to lead an independent research group that aims to understand the mechanistic basis of H2S effects in animals. The training provided by this award will allow me to develop lab management skills, publish research results and initiate a search for an independent position. In addition, the research plan will help me develop important skills using cytological and genetic techniques essential to fully utilize the power of the C. elegans system. In the first aim, I will test the hypothesis that H2S delays age-associated changes in C. elegans. These experiments will establish how H2S affects diverse biological processes in different tissue types. In the second aim, I will identify genes and pathways involved in the response to H2S. I will characterize mutations that constitutively express H2S-induced phenotypes, and determine which act in concert with sir-2.1 to influence lifespan. In a complementary approach, I will evaluate the role of genes identified in an RNAi-based screen that, like sir-2.1, are required for H2S-induced changes. Finally, I will use a microarray approach to identify factors affected by H2S-induced changes that are correlated with increased lifespan. These experiments will uncover molecular mechanism(s) by which H2S influences lifespan. Dr. Mark Roth's lab is an excellent training environment for my career development, owing to past success using cell biological and genetic analysis to understand biological processes in C. elegans. Moreover, the Roth lab has demonstrated that H2S has profound effects on mammalian physiology that can improve survival in changing conditions. RELEVANCE: Many conserved processes of aging have been identified by studying factors that influence lifespan in invertebrate models. This research program aims to identify the mechanism by which hydrogen sulfide increases lifespan in C. elegans. These studies may help explain processes that contribute to age- associated physiological decline that reduce the capacity to survive in a constantly fluctuating environment, which contribute increased mortality associated with aging.