Environmental Toxins and Genetic Factors in Parkinson Disease

帕金森病的环境毒素和遗传因素

基本信息

批准号：
8391725
负责人：
xugang xia
金额：
$ 33.39万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8391725
关键词：
Affect Age Aging Aging-Related Process Alleles Animal Model Animals Cessation of life Clinical Development Diagnosis Disease Disease Progression Disease model Disease susceptibility Dopamine Elderly Environmental Risk Factor Epidemiologic Studies Epigenetic Process Etiology Exposure to Functional disorder Gene Mutation Gene Targeting Genes Genetic Genetic Models Genetic Screening Homeostasis Incidence Individual Inherited Knowledge LRRK2 gene Life Link Midbrain structure Mitochondrial Proteins Modeling Modification Mus Mutate Mutation Neurons Occupational Exposure Onset of illness Other Genetics Oxidative Stress PINK1 gene Paraquat Parkin gene Parkinson Disease Parkinsonian Disorders Pathogenesis Patients Penetrance Pesticides Play Preventive Relative (related person)Risk Risk Factors Role Symptoms Syndrome System Testing Therapeutic Toxic Environmental Substances Twin Studies abstracting disease phenotype disorder risk dopaminergic neuron late disease onset mitochondrial dysfunction motor impairment neuron loss normal aging prevent therapeutic development

项目摘要

Project Abstract Parkinson disease (PD) is caused by progressive and substantial loss of dopaminergic neurons in the midbrain. Although PD symptoms can be alleviated by dopamine replenishment therapy, the available treatments cannot protect the neurons at risk or prevent the disease from progression because we have a limited knowledge on PD pathogenesis. Recent advance in genetic and epidemiological studies suggests a multifactorial etiology for PD. Besides aging, genetic and environmental factors are associated with the risk for PD. In animal models, exposure to the environmental toxin paraquat causes permanent and accumulative damage to dopaminergic system. Most PD cases have no causative mutation in the identified PD genes, but there may be epigenetic modifications to neuron-protective genes during aging process. How PD risky factors interact to cause the disease remains to be elucidated. One possible pathogenesis for PD is that the disease is caused by early exposure to environmental toxicants in combination with subsequent dysfunction of neuron-protective genes during aging process: early exposure to environmental toxins may reduce the threshold of developing PD; later dysfunction of one or more neuron-protective genes may accelerate the neuronal death, cross the reduced threshold for PD onset, and result in Parkinsonism. The genetic models for PD are mostly generated by constitutive mutation of targeted genes and thus cannot model temporal dysfunction of a gene later in life. To test this hypothetic pathogenesis of PD, we have created conditionally mutated mice to produce temporal and partial dysfunction of the targeted genes after the animals are exposed to environmental toxin in their early lives. We will use paraquat as a PD-related environmental toxin and PINK1 as a PD-linked gene. Dopamine likely plays an important role in PD pathogenesis because disturbance in dopamine homeostasis causes severely pathobiological conditions leading to neuronal death. Therefore, we will study the neuron-protective gene VMAT2 since VMAT2 plays a major role in dopamine homeostasis. This proposal will test how early exposure to environmental toxin superimposes deleterious effect on phenotypic expression subsequent to disturbance in dopamine homeostasis in later life, subsequent to later dysfunction of the PINK1 gene, or subsequent to later dysfunction of two neuron-protective genes. Results from this study will advance our understanding of PD pathogenesis and provide guidance to the development of therapeutic strategies for treating this devastating disease.

项目摘要帕金森病 (PD) 是由中脑多巴胺能神经元进行性和大量丧失引起的。虽然PD症状可以通过补充多巴胺疗法来缓解，但现有的治疗方法并不能保护处于危险中的神经元或防止疾病进展，因为我们对此的了解有限 PD发病机制。遗传和流行病学研究的最新进展表明，多因素病因 PD。除了衰老之外，遗传和环境因素也与帕金森病的风险有关。在动物模型中，接触环境毒素百草枯会对多巴胺能造成永久性和累积性损害系统。大多数PD病例在已识别的PD基因中没有致病性突变，但可能存在表观遗传突变衰老过程中神经元保护基因的修饰。 PD危险因素如何相互作用导致PD 疾病仍有待阐明。 PD 的一种可能的发病机制是该疾病是由早期暴露于环境毒物并随后导致神经元保护基因功能障碍衰老过程中：早期接触环境毒素可能会降低患PD的阈值；之后一种或多种神经元保护基因的功能障碍可能会加速神经元死亡，交叉减少 PD 发病阈值，并导致帕金森病。 PD的遗传模型主要是由目标基因的组成型突变，因此无法模拟基因在以后生命中的时间功能障碍。到为了测试这种假设的帕金森病发病机制，我们创造了条件突变的小鼠，以产生时间和动物在早期暴露于环境毒素后，目标基因部分功能障碍生活。我们将使用百草枯作为 PD 相关环境毒素，并使用 PINK1 作为 PD 相关基因。多巴胺多巴胺稳态紊乱可能在 PD 发病机制中发挥重要作用严重的病理生物学状况导致神经元死亡。因此，我们将研究神经元保护基因 VMAT2 因为 VMAT2 在多巴胺稳态中起着重要作用。该提案将测试多久暴露于环境毒素会对表型表达产生有害影响晚年多巴胺稳态紊乱，随后 PINK1 基因功能障碍，或随后两个神经元保护基因出现功能障碍。这项研究的结果将推动我们了解 PD 发病机制并为制定治疗策略提供指导治疗这种毁灭性的疾病。