daf-12 Target Genes during C. elegans aging

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于发展老年医学的学术生涯，研究重点是衰老的基本生物学。主要研究者已经完成了老年医学的临床培训，现在正在进行基本上是全职的研究，使用自由生活的线虫，C。elegans，研究衰老和寿命决定的遗传调控。培训计划包括结构化的教学工作和指导研究经验，旨在建立在主要研究者在DNA结合蛋白，转录调控和果蝇，果蝇，遗传学领域的先前研究经验的基础上。具体来说，该计划将开发新的研究能力，在生物学领域的老化，C。elegans遗传学和生物信息学/基因组学。 该提案还包括一项研究计划，旨在通过研究蠕虫来促进对衰老的理解。具体来说，研究将集中在孤儿核激素受体daf-12。这种受体的靶基因被预测在调节蠕虫的衰老中具有重要作用。首先确定daf-12调节寿命的时间，然后通过使用DNA微阵列分离在此作用窗口期间由daf-12直接调节的靶基因，并通过染色质免疫沉淀证实直接调节。分离的靶基因将根据其在衰老和对环境应激源（例如热、氧化应激、细菌病原体和UV辐射）的反应中的作用来表征。这些研究的目标将是确定在衰老中发挥作用的新基因，并开发最终了解这些基因的生化和分子功能所需的工具。 培训计划的最终目标是让主要研究者在老年医学部内制定一个基本的衰老生物学计划。对衰老过程中的生物化学事件以及生物体对这些事件的反应的进一步理解将大大提高我们对衰老过程以及衰老与疾病之间联系的理解。这种理解具有开发治疗方法的潜力，以解决衰老的负面影响或预防与衰老相关的疾病。此外，对衰老过程的更好理解将有助于了解老年患者和年轻患者之间的差异，特别是在疾病症状和治疗反应方面的差异。

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in Geriatrics with a research focus on the basic Biology of Aging. The principal investigator has completed clinical training in Geriatrics and is now pursuing essentially full-time research using the free-living nematode, C. elegans, to study the genetic regulation of aging and lifespan determination. The training program consists of structured didactic work and mentored research experiences designed to build upon the principle investigator's prior research experience in the areas of DNA binding proteins, transcriptional regulation, and fruitfly, Drosophila, genetics. Specifically the program will develop new research abilities in the areas of Biology of Aging, C. elegans genetics, and Bioinformatics/Genomics. The proposal also includes a research program which seeks to advance the understanding of aging through study of the worm. Specifically, study will focus on the orphan nuclear hormone receptor daf-12. Target genes for this receptor are predicted to have important roles in regulating the aging of the worm. The timing of daf-12 in regulating lifespan will initially determined, and then target genes directly regulated by daf- 12 during this window of action will be isolated by using DNA microarrays with confirmation of direct regulation by chromatin immunoprecipitation. Isolated target genes will be characterized with respect to their roles in aging and responses to environmental stressors, such as heat, oxidative stress, bacterial pathogens, and UV radiation. The goal of these studies will be to identify new genes with roles in aging and develop the tools needed to ultimately understand the biochemical and molecular functions of these genes. The ultimate goal of the training program is to allow the principal investigator to develop a program in the basic Biology of Aging within a Geriatrics Division. An improved understanding of the biochemical events involved in aging and the responses of an organism to these events will greatly enhance our understanding of the aging process and the link between aging and disease. This understanding holds the potential for the development of treatments to address the negative consequences of aging or to prevent diseases associated with aging. Additionally, an improved understanding of the aging process will provide insight into the differences between geriatric patients and younger patients especially with regards to differences in disease symptoms and response to treatments.