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）的运动神经元变性生物学相关的环境响应基因的功能变体。在遗传性运动神经元变性方面已经取得了相当大的进展，其中已经发现了SOD1和ALSIN等基因，并设计了合适的动物模型。然而，SALS和PLS的病因仍然不明确。两者都是复杂的疾病和遗传的，它被广泛接受的易感性编码在基因组中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与运动神经元变性病因相关的环境反应酶基因。PON基因簇（PON 1、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的突变是在皮质脊髓变性中引起的，表现为遗传性痉挛性截瘫（SPG5A）。脑桥是抗氧化剂和解毒农药，而CYP7B1被农业杀菌剂抑制。将完成对这些基因以及通过代谢途径与它们相关的基因的变异和与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中暴露于农药、杀真菌剂和其他相关压力因素的相互作用。这是一个新的机会，全面研究两个病因相关的环境反应基因在SALS和PLS。ALS患者1000例，PLS患者400例，对照组1000例。这项研究将建立遗传和环境风险，并导致合理的治疗和预防致残性致命疾病的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.