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：
8422569
负责人：
TEEPU SIDDIQUE
金额：
$ 24.65万
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/8422569
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）：肌萎缩性侧面硬化症（ALS）或Lou Gehrig病是一种致命的神经退行性疾病，主要影响中年和老年人。分别有两种形式的疾病，家族性（fals）和零星（SALS），分别占病例的10％和90％。 fal的遗传原因与多种基因的突变有关，例如超氧化物歧化酶，TDP-43，FUS，Optineurin，ubiquilin 2和C9orf72。然而，萨尔的病因仍然难以捉摸。几年前，我们的实验室发现，称为二氧蛋白酶的酶的基因中存在多态性，与sals相关。这些酶对某些农药和有毒剂排毒，因此成为与ALS相关的第一个与环境相关的基因。在血浆中对二氧蛋白酶和载脂蛋白L1的进一步研究表明，盐患者的水平显着升高。这些蛋白质是在具有多种功能在内的特定高密度脂蛋白（HDL）颗粒上发现的，包括脂质和胆固醇转运，并保护脂蛋白免受有害氧化的影响。在脑脊液（CSF）中也发现了类似的颗粒。因此，在此提案中，我们进一步表征了使用高通量技术在萨尔氏菌患者的血浆和CSF中选定的HDL物种的蛋白质组成。现在，我们可以在第一个时间确定神经退行性疾病中某些HDL蛋白的变化以及它们是否与疾病过程有关。我们还将确定HDL相关蛋白的基因是否包含与SALS风险相关的变体，以及这些变化是否与HDL蛋白水平的改变有关。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。这项工作的结果将开辟疗法的途径，以挽救潜在的功能障碍HDL，不仅在神经退行性疾病（例如ALS）中发现，而且在更常见的心血管和代谢疾病中。