Role of High Density Lipoprotein Particles in amyotrophic lateral sclerosis

高密度脂蛋白颗粒在肌萎缩侧索硬化症中的作用

• 批准号: 8469190
• 负责人: TEEPU SIDDIQUE
• 金额: $ 52.5万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2013-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469190
• 关键词: Affect; Age; Amyotrophic Lateral Sclerosis; Anabolism; Animals; Archives; Blood; Blood Circulation; Cardiovascular Diseases; Cerebrospinal Fluid; Cholesterol; Collection; DNA Resequencing; Data; Disease; Elderly; Enzyme Gene; Enzymes; Etiology; Event; Familial disease; Functional disorder; Gender; Gene Cluster; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genome; High Density Lipoproteins; Housing; Human; Inflammation; Insecticides; LDL Cholesterol Lipoproteins; Laboratories; Lead; Link; Lipids; Lipoproteins; Mass Spectrum Analysis; Metabolic Diseases; Methodology; Methods; Mus; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Pancreas; Patients; Pesticides; Physiology; Plasma; Process; Protein Analysis; Proteins; Proteome; Race; Risk; Role; Sampling; Serum; Single Nucleotide Polymorphism; Site; Superoxide Dismutase; Techniques; Testing; Time; Tissues; Training; Transgenic Model; Validation; Variant; Work; aryldialkylphosphatase; base; case control; cohort; gene environment interaction; genetic association; genetic variant; high throughput technology; middle age; oxidation; oxidative damage; oxidized lipid; particle; prospective; protein TDP-43; protein expression; protein function; response; rodent genome; stressor

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, and optineurin. 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. Because these enzymes detoxify certain pesticides and toxic agents, they became the first environmentally related genes that were linked to ALS. Further studies of the paraoxonase enzymes PON1 and PON3 in the plasma indicate that their levels are significantly elevated in SALS patients, although the activities were similar. PON1 and 3 are found on high density lipoprotein (HDL) particles that contain multiple proteins with several functions including lipid and cholesterol transport and protecting lipoproteins from deleterious oxidation. Similar particles are also found in the cerebrospinal fluid (CSF). Thus, the objectives of this proposal are to further characterize HDL-particles in the plasma and CSF of SALS patients using high throughput technologies that can quantify the levels of multiple proteins present in these particles. Thus, we can determine for the first time how HDL particle composition changes in a neurodegenerative disease and if they are causally linked to the disease process. We will also determine whether the genes for the HDL-associated proteins contain variants that are associated with risk of SALS and whether these changes are related to alterations in HDL particle composition. Using advanced gene targeting techniques, we will create ApoL1 transgenic model mice to study the effects of over expressing this HDL component. The results from this work will open paths to therapies that seek to rescue potential dysfunctional HDL states 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。有两种形式的疾病，家族性（FALS）和散发性（SALS），分别占病例的10%和90%。FALS的遗传原因与几个基因的突变有关，如超氧化物歧化酶，TDP-43，FUS和optineurin。然而，SALS的病因仍然难以捉摸。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。由于这些酶可以解毒某些杀虫剂和有毒物质，它们成为第一个与ALS相关的环境相关基因。对血浆中对氧磷酶PON 1和PON 3的进一步研究表明，它们的水平在SALS患者中显著升高，尽管活性相似。PON 1和PON 3存在于高密度脂蛋白（HDL）颗粒上，这些颗粒含有多种具有多种功能的蛋白质，包括脂质和胆固醇转运以及保护脂蛋白免受有害氧化。类似颗粒 也存在于脑脊液（CSF）中。因此，本提案的目的是使用高通量技术进一步表征SALS患者血浆和CSF中的HDL颗粒，该技术可以量化这些颗粒中存在的多种蛋白质的水平。因此，我们可以第一次确定HDL颗粒组成在神经退行性疾病中如何变化，以及它们是否与疾病过程有因果关系。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颗粒组成的改变有关。利用先进的基因靶向技术，我们将创建ApoL 1转基因小鼠模型，以研究过度表达这种HDL组分的影响。这项工作的结果将为寻求拯救不仅在ALS等神经退行性疾病中而且在更常见的心血管和代谢疾病中发现的潜在功能失调的HDL状态的疗法开辟道路。