Envronment-Sensitive genes in motoneuron degeneration

运动神经元变性中的环境敏感基因

基本信息

批准号：
7894804
负责人：
TEEPU SIDDIQUE
金额：
$ 75.84万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-16 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7894804
关键词：
Acute Intermittent Porphyria Address Adolescent Agriculture Amyotrophic Lateral Sclerosis Animal Model Antioxidants Attention Autopsy Barbiturates Biochemical Blood Blood - brain barrier anatomy Blood specimen Brain Chromosomes, Human, Pair 8 Clinic Clinical Collaborations Complex Corticospinal Tracts Counseling Disease Drug Metabolic Detoxication Drug usage Engineering Environment Environmental Exposure Environmental Risk Factor Enzymes Epidemiology Equilibrium Erythrocytes Etiology Exercise Exposure to Familial Amyotrophic Lateral Sclerosis Family Food Labeling Foundations Funding Gene Cluster Genes Genetic Genetic Predisposition to Disease Genetic Screening Genetic Variation Genome Goals Grant Hereditary Spastic Paraplegia Human Individual Industrial fungicide Infant Inherited Institutes Investigation Laboratories Lead Liver Lower Motor Neuron Disease Medical Metabolic Pathway Metabolism Molecular Genetics Motor Neurons Mutation Nerve Degeneration Neuromuscular Diseases Organophosphates Oxidative Stress Pathway interactions Peroxides Pesticides Phenotype Plasma Play Population Porphyrias Predisposition Prevention Primary Lateral Sclerosis Property Proteomics Public Health Research Research Infrastructure Research Personnel Resources Role Sampling Series Spastic Paraparesis Spinal Spinal Cord Sterols Stream System Testing Toxic effect Universities Variant Yang barbituric acid salt directed attention environmental stressor experience gene environment interaction loss of function mutation medical schools motor neuron degeneration nerve gas neurogenetics neurosteroids novel oxysterol 7-alpha-hydroxylase patient population prevent programs stressor trait

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to identify functional variants of environmentally responsive genes that are biologically relevant to motor neuron degeneration of sporadic amyotrophic lateral sclerosis (SALS) and primary lateral sclerosis (PLS). Considerable progress has been made in inherited motor neuron degeneration where genes such as SOD1 and ALSIN have been discovered and suitable animal models engineered. However etiology of SALS and PLS remains undefined. Both are complex disorders and a genetic and it is widely accepted susceptibility encoded in the genome interacts with environment stressors to produce motor neuron degeneration. These investigators have recently identified two sets of genes of environmentally responsive enzymes that are etiologically relevant to motoneuron degeneration. The PON cluster of genes (PON1, 2 and 3) was associated with SALS and this finding has been validated in four other studies. Mutations in the second gene, CYP7B1, are caused in corticospinal degeneration in a form of hereditary spastic paraplegia (SPG5A). PONs are antioxidant and detoxify pesticides, while CYP7B1 is inhibited by agricultural fungicides. A detailed examination of variations in these genes and in genes related to them by metabolic pathways and coexpression for association to SALS and PLS will be accomplished. Further, their interactions with environmental exposure to pesticides, fungicides and other relevant stressors will also be examined. This is a novel opportunity for a comprehensive study of two etiologically relevant environmentally responsive genes in SALS and PLS. 1000 ALS cases, 400 PLS cases and 1000 matched controls will participate in this study. This investigation will establish genetic and environmental risks, and lead to rational treatment and prevention of disabling fatal disorders of PLS and SALS.

描述（由申请人提供）：该项目的目的是鉴定与零星肌萎缩性侧面硬化症（SALS）和原发性侧面硬化症（PLS）的运动神经元变性有关的环境反应性基因的功能变异。在遗传性运动神经元变性中已经取得了长足的进步，在该变性中，已经发现了SOD1和ALSIN之类的基因并设计了合适的动物模型。但是，萨尔和PL的病因仍然不确定。两者都是复杂的疾病和一种遗传性，并且在基因组中被广泛接受的敏感性与环境压力源相互作用以产生运动神经元变性。这些研究者最近确定了与运动神经元变性有关的环境响应酶的两组基因。基因的PON簇（PON1、2和3）与SALS有关，这一发现在其他四项研究中得到了验证。第二个基因中的突变CYP7B1是在皮质脊髓变性的形式中以遗传性痉挛性截瘫（SPG5A）引起的。 PON是抗氧化剂和解毒的农药，而CYP7B1被农业杀菌剂抑制。通过代谢途径和与萨尔和PL的缔合的这些基因和与之相关的基因的变异的详细研究将得到实现。此外，还将检查它们与环境暴露于农药，杀菌剂和其他相关压力源的相互作用。这是对萨尔和PL中两个病因相关的环境响应基因进行全面研究的新机会。 1000例ALS病例，400例PLS案例和1000个匹配的对照将参与本研究。这项调查将建立遗传和环境风险，并导致PL和SAL的致命致命疾病的合理治疗和预防。