Mechanisms of the Response to Hydrogen Sulfide

描述（由申请人提供）：面对不断变化的环境条件，所有生物都必须保持体内平衡才能生存。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。动物细胞自然产生的硫化氢（H2S）可以延长秀丽隐杆线虫的寿命和耐热性。这个提议与我领导一个独立的研究小组的长期目标有关，该小组旨在了解H2S在动物中的作用的机制基础。这个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重要的技能，使用细胞学和遗传技术，以充分利用秀丽隐杆线虫系统的力量。在第一个目标中，我将测试H2S延迟秀丽隐杆线虫年龄相关变化的假设。这些实验将确定H2S如何影响不同组织类型中的各种生物过程。在第二个目标中，我将确定参与对H2S反应的基因和途径。我将描述组成表达h2s诱导表型的突变，并确定哪些与sir-2.1协同作用影响寿命。在一种补充方法中，我将评估在基于rnai的筛选中发现的基因的作用，如sir-2.1，这是h2s诱导变化所必需的。最后，我将使用微阵列方法来确定受h2s诱导的变化影响的因素，这些变化与寿命延长相关。这些实验将揭示H2S影响寿命的分子机制。Mark Roth博士的实验室为我的职业发展提供了良好的培训环境，因为他过去曾成功地利用细胞生物学和遗传分析来了解秀丽隐杆线虫的生物过程。此外，Roth实验室已经证明H2S对哺乳动物的生理有深远的影响，可以提高哺乳动物在变化条件下的存活率。相关性：通过研究无脊椎动物模型中影响寿命的因素，已经确定了许多保守的衰老过程。本研究项目旨在确定硫化氢延长秀丽隐杆线虫寿命的机制。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，这种生理衰退降低了在不断波动的环境中生存的能力，从而导致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.