daf-12 Target Genes during C. elegans aging

描述(由申请者提供)：本建议书描述了一项为期5年的老年医学学术生涯发展培训计划，重点是老年基础生物学的研究。首席研究员已经完成了老年病学的临床培训，现在基本上是全职研究，使用自由生活的线虫线虫，研究衰老和寿命决定的遗传规律。培训计划包括有组织的教学工作和指导研究经验，旨在建立在首席调查员在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。具体地说，该计划将在衰老生物学、线虫遗传学和生物信息学/基因组学领域发展新的研究能力。 该提案还包括一项研究计划，旨在通过对蠕虫的研究来促进人们对衰老的理解。具体地说，研究将集中在孤儿核激素受体daf-12上。据预测，该受体的靶基因在调节蠕虫的衰老方面具有重要作用。将初步确定daf-12调节寿命的时机，然后使用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，并确认通过染色质免疫沉淀直接调节。分离的靶基因将根据它们在衰老和对环境应激因素(如热、氧化应激、细菌病原体和紫外线辐射)的反应方面进行表征。这些研究的目标将是识别在衰老中起作用的新基因，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使首席研究人员能够在老年病学部内制定衰老基础生物学计划。更好地了解衰老过程中涉及的生化事件以及生物体对这些事件的反应将极大地增强我们对衰老过程以及衰老与疾病之间的联系的理解。这一认识具有开发治疗方法的潜力，以解决老龄化的负面后果或预防与老龄化有关的疾病。此外，对衰老过程的更好理解将有助于深入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对治疗的反应方面的差异。

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.