Envronment-Sensitive genes in motoneuron degeneration

描述(由申请人提供)： 该项目的目标是确定与散发性肌萎缩侧索硬化症(SALS)和原发性侧索硬化症(PLS)的运动神经元变性有关的环境反应基因的功能变异。遗传性运动神经元变性已经取得了相当大的进展，发现了SOD1和ALSIN等基因，并建立了合适的动物模型。然而，SALS和PLS的病因仍不明确。两者都是一种复杂的疾病，都是一种被广泛接受的遗传易感性，编码在基因组中的易感性与环境应激源相互作用，产生运动神经元变性。这些研究人员最近发现了两组环境反应酶基因，它们在病因学上与运动神经元变性有关。PON基因簇(PON1、2和3)与SALS相关，这一发现已在其他四项研究中得到验证。第二个基因CYP7B1的突变是由遗传性痉挛截瘫(SPG5A)引起的皮质脊髓变性引起的。PONS是抗氧化剂和解毒杀虫剂，而CYP7B1则被农用杀菌剂抑制。将完成对这些基因以及与它们相关的基因通过代谢途径的变异以及与SALS和PLS相关的共表达的详细检查。此外，还将研究它们与环境暴露于杀虫剂、杀菌剂和其他相关应激源的相互作用。这是一个全面研究SALS和PLS中两个病因学上相关的环境反应基因的新机会。1000例ALS患者、400例SLE患者和1000例配对对照参加本次研究。这项调查将确定遗传和环境风险，并导致合理治疗和预防致残性致死性疾病的PLS和SALS。

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.