Dopamine, Tryosine, and their Metabolites in Aging in Neurodegenerative Disease

描述（由申请人提供）：本申请描述了一个为期4年的培训计划，以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分子生物学和果蝇，果蝇，遗传学领域的先前研究经验。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。秀丽隐杆线虫遗传学、多巴胺生物学和分子毒理学。 该应用程序还包括一个研究计划，旨在通过使用蠕虫的研究来促进对衰老的理解。具体而言，研究将集中在4-羟苯丙酮酸双加氧酶基因，这是孤儿核激素受体daf-12的靶基因。该基因在长寿的daf-12突变体和长寿的daf-2胰岛素/IGF-1受体突变体中均下调，表明其在衰老调节中的作用。与此相一致，通过RNAi下调该单个基因可将蠕虫寿命延长高达30%。将使用RNA干扰研究和遗传学相结合的方法在蠕虫中研究寿命增加的机制。看来酪氨酸代谢物可能对组织有毒，这些代谢物水平的降低可能解释部分或全部寿命延长。该项目期间的一项平行调查将是调查酪氨酸衍生的神经递质多巴胺是否可能对蠕虫具有共同的毒性作用。 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 application describes a 4 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 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 principal investigator's prior research experience in the areas of molecular biology and fruit fly, Drosophila, genetics. Specifically the program will develop new research abilities in the areas of Biology of Aging, C. elegans genetics, Biology of Dopamine, and Molecular Toxicology. The application also includes a research program which seeks to advance the understanding of aging through studies using the worm. Specifically, study will focus on the 4-hydroxyphenylpyruvate dioxygenase gene which is a target gene of the orphan nuclear hormone receptor daf-12. This gene is down-regulated in both long-lived daf-12 mutants and in long-lived daf-2 insulin/IGF-1 receptor mutants suggesting a role in the regulation of aging. Consistent with this, down-regulation of this single gene by RNAi extends worm lifespan by up to 30%. The mechanisms involved in the increase in longevity will be investigated in worms using a combination of RNA interference studies and genetics. It appears that tyrosine metabolites may be toxic to tissues and reduction of these metabolite levels may explain some or all of the extension of lifespan. A parallel investigation during the project will be to investigate whether the tyrosine-derived neurotransmitter dopamine may share common toxic effects on worms. 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.