Cholesterol Biomarkers and Oxysterols in Multiple Sclerosis Progression

多发性硬化症进展中的胆固醇生物标志物和氧甾醇

• 批准号: 9168029
• 负责人: MURALI RAMANATHAN
• 金额: $ 23.93万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9168029
• 关键词: 27-hydroxycholesterol; 7-ketocholesterol; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Injuries; Cells; Cholesterol; Cholesterol Homeostasis; Chronic Disease; Clinical; Clinical Research; Clinical assessments; Data; Demyelinations; Dependence; Disease; Disease Progression; Event; Frequencies; Functional disorder; Goals; Homeostasis; Hydroxycholesterols; Immune; Immune response; Inflammation; Intervention; Lesion; Life Style; Ligands; Lipids; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Mediator of activation protein; Molecular; Molecular Target; Multiple Sclerosis; Myelin; Myelin Sheath; Nerve Degeneration; Neuraxis; Neurons; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Physically Handicapped; Process; Relapse; Relapsing-Remitting Multiple Sclerosis; Research; Research Design; Role; Sampling; Serum; Signal Transduction; Signaling Molecule; Staging; Therapeutic; base; cerebral atrophy; cognitive disability; cohort; disability; follow-up; interest; lipoprotein cholesterol; liquid chromatography mass spectrometry; multiple sclerosis patient; targeted treatment; transcription factor

ABSTRACT Multiple sclerosis (MS) is a chronic disease of the central nervous system that causes cognitive and physical disability. MS is characterized by demyelination, inflammation, lesion formation and neurodegeneration. Cholesterol is a key lipid in the myelin sheath and is critical for myelin function. Disease progression is a significant challenge in MS therapeutics because the currently available immunomodulatory drugs do not halt the neurodegenerative processes that are responsible for brain atrophy and disability progression. Compelling recent evidence from our research indicates that serum cholesterol and lipoprotein profiles are associated with disability changes and magnetic resonance imaging (MRI) measures of lesion formation and neurodegeneration in patients with established MS and in the earliest stages of MS following the first demyelinating event. The mechanisms underlying these pathophysiological associations of cholesterol biomarkers with brain injury in MS are not known. Based on our preliminary results, we hypothesize that the associations between serum cholesterol and brain injury in MS are driven by key contributions from oxysterols, which are promising molecular mediators for these pathophysiological associations because they can cross the blood brain barrier and also regulate cholesterol homeostasis in the brain and the periphery. Oxysterols, particularly 24-hydroxy cholesterol (24HC), 27-hydroxy cholesterol (27HC), 7α-hydroxy cholesterol (7αHC) and 7-ketocholesterol (7KC) are of interest because they are potent transcription factor ligands and regulatory mediators of cholesterol and immune homeostasis. The goal is to investigate the role of oxysterols and cholesterol pathway biomarkers in MS disease progression. In Specific Aim 1, we will compare the longitudinal changes in a focused panel of major oxysterols in serum at baseline and after 5 years in MS patients compared to controls and investigate their associations with serum lipids. In Specific Aim 2, we will measure select downstream molecular targets of oxysterol signaling and identify the oxysterols and oxysterol target molecules associated with progression of brain injury over 5 years. We hypothesize that decreased 24-hydroxy cholesterol, decreased 7α-hydroxy cholesterol, increased 27- hydroxy cholesterol and increased 7-ketocholesterol levels in serum are associated with greater neurodegeneration. The study will use serum samples obtained at baseline and 5-year follow-up from 150 MS patients and 50 controls. The patients' serum samples will be analyzed for oxysterol and oxysterol targets. Aim 1 will leverage sensitive and selective state-of-the-art liquid chromatography-mass spectrometry assays capable of simultaneously quantitating multiple oxysterols. We will have longitudinal clinical and quantitative MRI data for this cohort. When successfully completed, this project will identify molecular mechanisms that will better define the pathophysiological role of the cholesterol pathway in MS disease progression.

摘要 多发性硬化症（MS）是一种慢性中枢神经系统疾病， 残疾。MS的特征在于脱髓鞘、炎症、病变形成和神经变性。 胆固醇是髓鞘中的关键脂质，对髓鞘功能至关重要。 疾病进展是MS治疗中的重大挑战，因为目前可用的治疗方法是有效的。 免疫调节药物不能阻止导致脑萎缩的神经退行性过程 和残疾进展。我们最近的研究证据表明，血清胆固醇和 脂蛋白谱与残疾变化和磁共振成像（MRI）测量相关， 已确诊MS患者和MS早期阶段的病变形成和神经变性 在第一次脱髓鞘事件之后。这些病理生理学关联的潜在机制 胆固醇生物标志物与MS脑损伤的关系尚不清楚。基于我们的初步结果，我们假设 MS患者血清胆固醇和脑损伤之间的关联是由以下因素的关键贡献驱动的： 氧化固醇，这是有前途的分子介质，这些病理生理协会，因为他们 可以穿过血脑屏障，也可以调节脑和外周的胆固醇稳态。 氧固醇，特别是24-羟基胆固醇（24 HC）、27-羟基胆固醇（27 HC）、7α-羟基胆固醇 （7αHC）和7-酮胆固醇（7 KC）是令人感兴趣的，因为它们是有效的转录因子配体， 胆固醇和免疫稳态的调节介质。我们的目标是调查氧化固醇的作用， 和胆固醇途径生物标志物。 在具体目标1中，我们将比较在以下时间点血清中主要氧化固醇的集中面板的纵向变化： MS患者基线和5年后与对照组相比，并研究其与血清 脂质。在具体目标2中，我们将测量选择的氧化固醇信号传导的下游分子靶点， 确定与脑损伤进展相关的氧固醇和氧固醇靶分子超过5年。 我们假设，降低24-羟基胆固醇，降低7α-羟基胆固醇，增加27-羟基胆固醇， 血清中羟基胆固醇和7-酮胆固醇水平的增加与更大的 神经变性本研究将使用150例MS患者在基线和5年随访时获得的血清样本 患者和50名对照。将分析患者血清样本的氧化固醇和氧化固醇目标。目的 1将利用灵敏和选择性的最先进的液相色谱-质谱分析 能够同时定量多种氧甾醇。我们将有纵向的临床和定量的 该队列的MRI数据。 当成功完成后，该项目将确定分子机制，将更好地定义 胆固醇途径在MS疾病进展中的病理生理作用。