Mechanisms of the Response to Hydrogen Sulfide

对硫化氢的反应机制

• 批准号: 7569757
• 负责人: Dana L Miller
• 金额: $ 9万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569757
• 关键词: Affect; Age; Aging; Aging-Related Process; Animals; Applied Genetics; Award; Biological; Biological Assay; Biological Process; Caenorhabditis elegans; Cells; Chromosomes; Data; Data Analyses; Disease; Environment; Exhibits; Exposure to; Face; Foundations; Genes; Genetic; Genetic Models; Genetic Techniques; Genomics; Goals; Histocompatibility Testing; Homeostasis; Homologous Gene; Hydrogen Sulfide; Immune System and Related Disorders; Infection; Injury; Instinct; Insulin; Invertebrates; Lead; Learning; Longevity; Mediating; Mentors; Messenger RNA; Metabolic; Microarray Analysis; Modeling; Molecular; Molecular Genetics; Monitor; Mutation; Organism; Pathway interactions; Phase; Phenotype; Physiological; Physiology; Positioning Attribute; Predisposition; Process; Psyche structure; Publishing; RNA Interference; Research; Resistance; Role; Signal Pathway; Sum; System; Techniques; Testing; Training; Transgenic Animals; base; career development; dietary restriction; environmental change; experience; gene function; genetic analysis; improved; insight; interest; mitochondrial dysfunction; mortality; muscle degeneration; mutant; novel; polyglutamine; programs; protein aggregation; reproductive; research study; response; senescence; skills; success; tumor

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.

描述（由申请人提供）：所有生物体必须在不断变化的环境条件下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。硫化氢（H2S）是由动物细胞自然产生的，可以增加C.优美的这个提议与我的长期目标有关，即领导一个独立的研究小组，旨在了解H 2 S对动物影响的机制基础。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，并开始寻找一个独立的职位。此外，研究计划将帮助我发展重要的技能，使用细胞学和遗传学技术，以充分利用C。elegans系统在第一个目标，我将测试的假设，即硫化氢延迟年龄相关的变化，在C。优雅的这些实验将确定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H2S反应的基因和途径。我将描述组成性表达硫化氢诱导表型的突变，并确定哪些与sir-2.1共同影响寿命。在一个补充的方法中，我将评估在基于RNAi的筛选中鉴定的基因的作用，如sir-2.1，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绝佳的培训环境，因为过去成功地使用细胞生物学和遗传分析来了解C中的生物过程。优美的此外，罗斯实验室已经证明，H2S对哺乳动物的生理学有深远的影响，可以提高在不断变化的条件下的生存能力。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。这项研究计划旨在确定硫化氢增加C寿命的机制。优雅的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。