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 的遗传原因与超氧化物歧化酶、TDP-43、FUS 和 optineurin 等多个基因的突变有关。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。由于这些酶可以解毒某些农药和有毒物质，因此它们成为第一个与 ALS 相关的环境相关基因。对血浆中对氧磷酶 PON1 和 PON3 的进一步研究表明，尽管活性相似，但 SALS 患者中它们的水平显着升高。 PON1 和 3 存在于高密度脂蛋白 (HDL) 颗粒上，该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。相似颗粒 也存在于脑脊液（CSF）中。因此，本提案的目标是使用高通量技术进一步表征 SALS 患者血浆和脑脊液中的 HDL 颗粒，这些技术可以量化这些颗粒中存在的多种蛋白质的水平。因此，我们可以首次确定 HDL 颗粒成分在神经退行性疾病中如何变化，以及它们是否与疾病过程存在因果关系。我们还将确定 HDL 相关蛋白的基因是否包含与 SALS 风险相关的变异体，以及这些变化是否与 HDL 颗粒组成的改变有关。利用先进的基因打靶技术，我们将创建 ApoL1 转基因模型小鼠，以研究过度表达这种 HDL 成分的影响。这项工作的结果将为寻求挽救潜在的功能失调 HDL 状态的疗法开辟道路，这些状态不仅存在于 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。