FETAL AND ENVIRONMENTAL BASIS OF PARKINSON'S DISEASE

帕金森病的胎儿和环境基础

基本信息

批准号：
7230013
负责人：
CLIVEL G. CHARLTON
金额：
$ 15.89万
依托单位：
MEHARRY MEDICAL COLLEGE
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：
2006-03-03 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7230013
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-Methyl-4-phenylpyridinium Adolescent Adult Age Anatomy Basal Ganglia Biochemistry Biological Birth Chemicals Condition DNA Degenerative Disorder Dopamine Embryo Epigenetic Process Exposure to Fetus Formaldehyde Formic Acids Goals Intervention Juvenile Parkinson Disease Lead Life Longevity Melanocytic nevus Methanol Methionine Methylation Mitotic Modeling Mole the mammal Molecular Motor Motor Activity Mus Nature Neurons Numbers Outcome Parkinson Disease Patient currently pregnant Perinatal Exposure Phenotype Poison Population Pregnancy Research Personnel Rodent Staging Stress Symptoms System Testing Tissues Toxic effect Toxin Tyrosine 3-Monooxygenase age related base critical developmental period day dopaminergic neuron early onset expectation fetal formic acid in utero neurogenesis nigrostriatum precursor cell prevent programs pup resilience therapy development tool

项目摘要

DESCRIPTION (provided by applicant): This study will test the proposition that toxic substances are involved in the cause of idiopathic Parkinson's disease (PD) by inducing, early in life, a less resilient but functional set of nigrostriatal (IMS) dopamine (DA) neurons that cannot withstand the stress placed on them later in life. Two stages of afflictions are therefore involved. The 1st is a predisposing, susceptible, vulnerable or sensitizing stage, occurring early in life, causing mostly epigenetic changes that impair the phenotype and/or reduce the number of the NS DA neurons. The 2nd, precipitating/inducing stage occurs when age-related wear-and-tear or other interventions damage the already susceptible NS DA neurons and precipitate the symptoms of PD. This hypothesis may explain the age-relatedness and sporadic nature o. PD. It may also explain juvenile (early onset) and adult onset PD, for the simple reason that for juvenile PD the 1st/susceptible stage will be more severe and is closer to threshold. Accordingly, the 2nd/inducing stage, of a constant intensity, will precipitate PD at an earlier age. The specific aims are: (1). To induce the 1st stage by administering methanol (MeOH) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to pregnant mice during the vulnerable period of the differentiation/neurogenesis of the NS DA neurons of the fetuses (about gestation days 8-12). The intent is to cause subtle or subthreshold changes to the NS DA neurons of the offsprings without impairing motor functions. (2).To induce the 2nd or precipitating stage in the mature MeOH-or MPTP-treated offsprings by increasing biological methylation via S-adenosyl-L-methionine (SAM) or challenging with MPTP. These will cause further or threshold level harm to the NS DA neurons. MPTP is a precursor for the toxin, 1-methyl-4-phenylpyridinium that targeted the NS DA neurons and is fetotoxic. MeOH is an embryo-toxin (Rogers and Mole, 1997), causes basal ganglia toxicity (Guggenhein et al, 1971; Dewitt and Martin 1988; Ley and Gali 1983; Mozaz et al, 1991; Aziz et al, 2002), covalently reacts with DNA (Chung et al, 2004) and reduces total DNA (Abbot et al, 1994). It freely crosses tissue barriers and it is a precursor for formaldehyde and formic acid. The functions, anatomy and biochemistry of the basal ganglia will be studied to assess the phenotypic changes associated with the sensitization stage induced in utero as well as to verify the precipitated PD-like changes. A new model for PD may be identified and the results may lead to the development of interventions to prevent or delay similar toxicities. The approaches will find utility in the study of other degenerative disorders by focusing on other neuronal groups.

描述（由申请人提供）：本研究将检验以下主张，即有毒物质与特发性帕金森氏病（PD）有关，通过诱导生命的早期，这是一种弹性较低但功能较低的Nigrostriatal（IMS）多巴胺（DA）神经元，无法承受对它们较晚的压力。因此，涉及两个苦难的阶段。第一是生命早期发生的诱人，易感性，脆弱或致敏阶段，主要导致表观遗传变化，从而损害了表型和/或减少NS DA神经元的数量。当与年龄相关的磨损或其他干预措施损害已经敏感的NS DA神经元并沉淀PD的症状时，第二阶段的沉淀/诱导阶段发生。该假设可以解释与年龄相关性和零星性质o。 PD。它也可以解释少年（早期发作）和成人发作PD，出于简单的原因，对于少年PD，第一/易感阶段将更加严重，并且更接近阈值。因此，恒定强度的第二/诱导阶段将在较早的年龄中沉淀出PD。具体目的是：（1）。通过将甲醇（MeOH）或1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）施用到胎儿的脆弱时期（大约是8-12天的NS DA神经元的分化/神经发生）。目的是在不损害运动功能的情况下对后代的NS DA神经元引起微妙或亚阈值的变化。（2）。通过通过S-腺苷-l-甲硫氨酸（SAM）增加生物甲基化或用MPTP挑战，在成熟的MeOH或MPTP处理后的后代中诱导第二或沉淀阶段。这些将对NS DA神经元造成进一步或阈值的损害。 MPTP是靶向NS DA神经元且具有fetotoxoxic的毒素1-甲基-4-苯基吡啶丁的前体。 MeOH is an embryo-toxin (Rogers and Mole, 1997), causes basal ganglia toxicity (Guggenhein et al, 1971; Dewitt and Martin 1988; Ley and Gali 1983; Mozaz et al, 1991; Aziz et al, 2002), covalently reacts with DNA (Chung et al, 2004) and reduces total DNA (Abbot et al, 1994).它可以自由地越过组织屏障，并且是甲醛和甲酸的前体。将研究基底神经节的功能，解剖学和生物化学，以评估与子宫内诱导的敏化阶段相关的表型变化，并验证沉淀的PD样变化。可以确定一个新的PD模型，结果可能导致开发预防或延迟相似毒性的干预措施。这些方法将通过关注其他神经元组来研究其他退行性疾病的实用性。