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

多巴胺、酪氨酸及其代谢物在神经退行性疾病中的衰老作用

基本信息

批准号：
7643177
负责人：
ALFRED L FISHER
金额：
$ 19.23万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-15 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7643177
关键词：
3,4-Dihydroxyphenylacetic Acid 4-Hydroxyphenylpyruvate Dioxygenase Accounting Acetoacetates Acute Address Affect Age Aging Aging-Related Process Alkaptonuria Alleles Animals Applications Grants Area Basal Ganglia Biochemical Biochemical Pathway Biochemistry Bioinformatics Biological Models Biology Biology of Aging Bradykinesia Caenorhabditis elegans Caloric Restriction Cell Culture Techniques Cell Death Cessation of life Chemicals Cholinergic Receptors Chronic Citric Acid Cycle Clinical Cloning Commit DNA Data Decarboxylation Degradation Pathway Detection Development Diet Dioxygenases Disease Dopamine Down-Regulation Drosophila genus Drug Metabolic Detoxication Eating Effectiveness Elderly Endocrine Enzymes Escherichia coli Etiology Eukaryota Event Exposure to Facies Felis catus Fertility Fumarates Fumarylacetoacetase Fumarylacetoacetase Deficiency Disease Future Gene Expression Gene Mutation Gene Targeting Genes Genetic Genetic Screening Geriatrics Goals Gonadal structure Growth Heating High Pressure Liquid Chromatography Hodgkin Disease Homologous Gene Hydroxylation Inborn Errors of Metabolism Individual Infertility Insulin Insulin-Like-Growth Factor I Receptor Intervention Intestines Investigation Life Ligand Binding Link Liver Longevity Mammals Mango - dietary Maps Masks Measurement Measures Mediating Medical Mentors Metabolic Methionine Methods Microarray Analysis Molecular Molecular Biology Molecular Toxicology Monitor Morphology Mus Muscle Rigidity Mutagenesis Mutate Mutation Nematoda Neurodegenerative Disorders Neurologic Neurons Neurotransmitters Northern Blotting Nuclear Hormone Receptors Organism Orphan Oxidative Stress Oxidopamine Parkinson Disease Pathway interactions Patients Pattern Phenotype Phenylalanine Phenylalanine Hydroxylase Physiological Play Principal Investigator Production Program Development Protein Biosynthesis Proteins Pump RNA RNA Interference Reaction Regulation Reporter Research Resistance Rest Tremor Role Sensory Signal Pathway Signal Transduction Structure Substantia nigra structure Symptoms Synapses System Testing Time Tissues Toxic effect Training Training Programs Transgenes Transgenic Animals Tyrosine Tyrosine Aminotransferase Work absorption base biological adaptation to stress career design dietary restriction dopamine quinone dopamine toxicity dopamine transporter dopaminergic neuron enzyme deficiency experience feeding gain of function homogentisate improved in vivo insight interest intervention effect loss of function mutant novel older patient oxidation p-hydroxyphenylpyruvate prevent programs promoter receptor repaired research study response restoration steroid hormone stressor succinylacetone theories therapy development

项目摘要

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.

描述（由申请人提供）：本申请描述了一项为期4年的培训计划，以开发老年医学学术职业生涯，研究重点是衰老的基本生物学。首席研究员已经完成了老年医学的临床培训，现在正在使用秀丽隐杆线虫C. elegrans进行研究，以研究对衰老和寿命确定的遗传调节。培训计划由结构化的教学工作组成，并指导了研究经验，旨在基于主要研究者在分子生物学和果蝇领域的先前研究经验，果蝇，遗传学。具体而言，该计划将在衰老，秀丽隐杆线虫遗传学，多巴胺生物学和分子毒理学领域发展新的研究能力。该应用程序还包括一个研究计划，该计划旨在通过使用蠕虫的研究来提高对衰老的理解。具体而言，研究将集中于4-羟基苯基丙酮酸二加氧酶基因，该基因是孤儿核激素受体DAF-12的靶基因。该基因在长寿命的DAF-12突变体和长寿命DAF-2胰岛素/IGF-1受体突变体中都下调，这表明在衰老调节中起作用。与此一致，RNAi对这个单个基因的下调可扩展蠕虫寿命高达30％。 RNA干扰研究和遗传学的组合将研究寿命增加的机制。看来酪氨酸代谢物可能对组织有毒，而这些代谢物水平的降低可能解释了寿命的某些或全部延伸。该项目期间的平行研究将是研究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允许首席研究人员在老年医学部门内制定基本衰老生物学计划。对衰老涉及的生化事件以及生物体对这些事件的反应的增强理解将大大增强我们对衰老过程以及衰老与疾病之间的联系的理解。这种理解具有开发治疗的潜力，以解决衰老的负面后果或预防与衰老相关的疾病。此外，对衰老过程的改进理解将为老年患者和年轻患者之间的差异提供深入的了解，尤其是在疾病症状和对治疗的反应方面。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Retrofitting ampicillin resistant vectors by recombination for use in generating C. elegans transgenic animals by bombardment.

DOI：
10.1016/j.plasmid.2009.06.001
发表时间：
2009-09
期刊：
Plasmid
影响因子：
2.6
作者：
Ferguson AA;Fisher AL
通讯作者：
Fisher AL

DAF-12 regulates a connected network of genes to ensure robust developmental decisions.

DOI：
10.1371/journal.pgen.1002179
发表时间：
2011-07
期刊：
PLoS genetics
影响因子：
4.5
作者：
Hochbaum D;Zhang Y;Stuckenholz C;Labhart P;Alexiadis V;Martin R;Knölker HJ;Fisher AL
通讯作者：
Fisher AL

Generation of transgenic C. elegans by biolistic transformation.