Association of ALS to gene-environment mediated changes in HDL proteins

ALS 与基因环境介导的 HDL 蛋白变化的关联

基本信息

批准号：
8609030
负责人：
TEEPU SIDDIQUE
金额：
$ 61.33万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2017-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8609030
关键词：
Affect Age Amyotrophic Lateral Sclerosis Anabolism Animals Apolipoproteins Archives Blood C9ORF72 Cardiovascular Diseases Cell Culture Techniques Cells Cerebrospinal Fluid Cholesterol Collection DNA Resequencing Data Disease Elderly Environment Enzyme Gene Enzymes Etiology Event Familial disease Fatty acid glycerol esters Functional disorder Gender Gene Cluster Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Polymorphism Genetically Engineered Mouse Genetically Modified Animals Genome Genotype High Density Lipoproteins Homeostasis Human Inflammation Insecticides Laboratories Lead Link Lipids Lipoproteins Low-Density Lipoproteins Mass Spectrum Analysis Measures Mediating Metabolic Diseases Methodology Methods Mus Mutation Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Pancreas Patients Pesticides Physiology Plasma Process Proteins Proteome Race Risk Sampling Serum Single Nucleotide Polymorphism Site Superoxide Dismutase Techniques Testing Time Tissues Training Transgenic Model Variant Work aryldialkylphosphatase base case control cohort genetic association genetic variant high throughput technology middle age oxidation oxidative damage oxidized lipid particle prospective protein TDP-43 protein function public health relevance response rodent genome stressor ubiquilin vector

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) or Lou Gehrig disease is a fatal neurodegenerative disease that primarily affects mid-life and older adults. There are two forms of disease, familial (FALS) and sporadic (SALS), respectively comprising 10% and 90% of cases, respectively. The genetic causes of FALS have been linked to mutations in several genes such as superoxide dismutase, TDP-43, FUS, optineurin, ubiquilin 2 and C9ORF72. The etiology of SALS, however, remains elusive. A few years ago our laboratory found that there were polymorphisms in genes for enzymes called paraoxonases that were associated with SALS. These enzymes detoxify certain pesticides and toxic agents, and thus became the first environmentally related genes linked to ALS. Further studies of the paraoxonases and apolipoprotein L1 in the plasma indicate that their levels are significantly elevated in SALS patients. These proteins are found on specific high density lipoprotein (HDL) particles that have several functions including lipid and cholesterol transport and protecting lipoproteins from deleterious oxidation. Similar particles are also found in the cerebrospinal flui (CSF). Thus, in this proposal we further characterize the protein composition of selected HDL species in the plasma and CSF of SALS patients using high throughput technologies. We can now, for the first, time determine how certain HDL proteins change in a neurodegenerative disease and if they are linked to the disease process. We will also determine whether the genes for HDL-associated proteins contain variants that are associated with risk of SALS and whether these changes are related to alterations in HDL protein levels. Mechanisms of the deleterious effects of these changes will be studied in cell culture and genetically engineered mice. Results from this work will open paths to therapies to rescue potential dysfunctional HDL found not only in neurodegenerative disease such as ALS but also in more common cardiovascular and metabolic diseases.

描述（由申请人提供）：肌萎缩侧索硬化症（ALS）或卢伽雷氏病是一种致命的神经退行性疾病，主要影响中年和老年人。疾病有两种形式：家族性 (FALS) 和散发性 (SALS)，分别占病例的 10% 和 90%。 FALS 的遗传原因与多个基因的突变有关，例如超氧化物歧化酶、TDP-43、FUS、optineurin、泛素 2 和 C9ORF72。然而，SALS 的病因仍不清楚。几年前，我们的实验室发现与 SALS 相关的对氧磷酶基因存在多态性。这些酶可以解毒某些农药和有毒物质，因此成为第一个与 ALS 相关的环境相关基因。对血浆中对氧磷酶和载脂蛋白 L1 的进一步研究表明，SALS 患者中它们的水平显着升高。这些蛋白质存在于特定的高密度脂蛋白 (HDL) 颗粒上，具有多种功能，包括脂质和胆固醇运输以及保护脂蛋白免受有害氧化。脑脊液（CSF）中也发现了类似的颗粒。因此，在本提案中，我们使用高通量技术进一步表征 SALS 患者血浆和脑脊液中选定 HDL 种类的蛋白质组成。现在，我们第一次可以确定某些 HDL 蛋白在神经退行性疾病中如何变化，以及它们是否与疾病过程相关。我们还将确定 HDL 相关蛋白的基因是否包含与 SALS 风险相关的变异，以及这些变化是否与 HDL 蛋白水平的变化有关。这些变化的有害影响的机制将在细胞培养和基因工程小鼠中进行研究。这项工作的结果将为挽救潜在功能失调的高密度脂蛋白（HDL）的治疗开辟道路，这种功能障碍不仅存在于肌萎缩侧索硬化症（ALS）等神经退行性疾病中，而且还存在于更常见的心血管和代谢疾病中。