CNDP1 IN GWI (CARNOSINE DIPEPTIDASE 1 - GULF WAR ILLNESS)

GWI 中的 CNDP1（肌肽二肽酶 1 - 海湾战争疾病）

• 批准号: 7952011
• 负责人: JAMES N BARANIUK
• 金额: $ 1.47万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7952011
• 关键词: Address; Alleles; Amino Acids; Antioxidants; Bicarbonates; Biological; Biological Markers; Carnosine; Cell Culture Techniques; Cells; Cerebrospinal Fluid; Chronic Fatigue Syndrome; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Cross-Sectional Studies; Cyanobacterium; Dipeptidases; Dipeptides; Dose; Double-Blind Method; Dust; Fatigue; Functional disorder; Funding; Genetic; Genotype; Glutamates; Glutamine; Grant; Gulf War; Hand; Hyperalgesia; Injury; Institution; Isometric Exercise; Lethal Dose 50; Mediating; Military Personnel; Modeling; Muscle; Muscle function; Neuroblastoma; Oral; Oxidants; Pain; Pathogenesis; Placebos; Plasma; Plasma Proteins; Proteins; Proteome; Proteomics; Quality of life; Recruitment Activity; Research; Research Personnel; Resources; Role; SF-36; Safety; Set protein; Sleep; Source; Statistical Models; Symptoms; Toxic effect; Toxin; United States National Institutes of Health; Visceral pain; Water; cohort; grasp; homocarnosine; improved; killings; neurotoxic; neurotoxicity; placebo controlled study; randomized placebo controlled trial; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background: Our cerebrospinal fluid proteomics studies identified a specific set of proteins (GWI/CFS proteome) in two separate cohorts of subjects with co-existing Gulf War Illness (GWI) and chronic fatigue syndrome (CFS) compared to healthy control subjects. One critical protein, carnosine dipeptidase 1 (CNDP1), was detected significantly more frequently in GWI (n=4/9) than in healthy controls (n=1/12) Aim 1.b.ii: Advanced statistical modeling of the plasma proteins to identify unique biomarkers of GWI. Hypothesis 1.c: A statistical model of CNDP1 genotype, GWI-related plasma proteins, pain, systemic hyperalgesia, autonomic and muscle function, sleep, quality of life, fatigue and other complaints will predict GWI or subsets of GWI subjects. Aim 1.c: Determine if the LB6B and LB7B alleles predict the plasma proteome, pain, autonomic and muscle dysfunction (isometric hand grip), activity (Actiwatch), quality of life (SF-36), sleep, fatigue, and other common symptoms in GWI. Plan 2: Recruit 100 GWI to a double-blind, placebo-controlled randomized study of oral carnosine. Hypothesis 2: Carnosine improves pain, sleep, and activity after 6 months. Aim 2: Determine if oral carnosine significantly improves activity (Actiwatch), scores for fatigue, pain, sleep, and SF-36 quality of life domains compared to placebo. Plan 3: Genotype neuroblastoma cells for CNDP1. Assess antioxidant effects in cell culture. Hypothesis 3: Carnosine and homocarnosine will protect neuroblastoma cells from oxidant injury and glutamate-induced neurotoxicity. Aim 3: Determine the lethal dose for 50% killing of neuroblastoma cells for HB2BOB2B and glutamate. Determine the dose response effects of carnosine and homocarnosine on these toxic agents. Plan 4: Culture neuroblastoma cells with BMAA, HCO3-, homocarnosine, and carnosine. Hypothesis 4: BMAA from Cyanobacterium in brackish water and dust was toxic in military personnel who have longer CNDP1 genotypes (LB6B, LB7B) and reduced antioxidant dipeptides. BMAA interacts with bicarbonate to form a glutaminergic toxin. Aim 4: Study the biological interactions of these antioxidants on BMAA and bicarbonate toxicity. Impact: The cross-sectional study will identify genetic (CNDP1 alleles) and proteomic biomarkers in GWI. The antioxidant and neuromodulatory effects of homocarnosine, carnosine, and their amino acids provide the rationale for our double-blind, placebo-controlled study of oral carnosine as a treatment for GWI. Both safety and efficacy issues will be addressed prospectively. Neuroblastoma cells will be a model for understanding the functions of these dipeptides and CNDP1, their role in protecting against oxidant and glutamine-mediated neurotoxicity, and the potential neurotoxic effects of cyanobacterial BMAA in GWI and ALS-PD pathogenesis.,

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 背景资料：我们的脑脊液蛋白质组学研究确定了一组特定的蛋白质（GWI/CFS蛋白质组）在两个单独的队列的受试者与健康对照组相比，同时存在海湾战争疾病（GWI）和慢性疲劳综合征（CFS）。一个关键蛋白，肌肽二肽酶1（CNDP 1），被检测到显着更频繁地在GWI（n=4/9）比健康对照（n=1/12）目的1.b.ii：先进的血浆蛋白的统计建模，以确定独特的生物标志物GWI。假设1.c：CNDP 1基因型、GWI相关血浆蛋白、疼痛、全身性痛觉过敏、自主神经和肌肉功能、睡眠、生活质量、疲劳和其他主诉的统计模型将预测GWI或GWI受试者的子集。目标1.c：确定LB 6 B和LB 7 B等位基因是否可预测血浆蛋白质组、疼痛、自主神经和肌肉功能障碍（等长握力）、活动（Actiwatch）、生活质量（SF-36）、睡眠、疲劳和GWI中的其他常见症状。计划2：招募100名GWI参加一项口服肌肽的双盲、安慰剂对照随机研究。假设2：肌肽在6个月后改善疼痛，睡眠和活动。目标二：确定与安慰剂相比，口服肌肽是否显著改善活动（Actiwatch），疲劳，疼痛，睡眠和SF-36生活质量领域的评分。计划3：CNDP 1的神经母细胞瘤细胞基因型。评估细胞培养中的抗氧化作用。假设3：肌肽和高肌肽将保护神经母细胞瘤细胞免受氧化损伤和谷氨酸诱导的神经毒性。目的3：确定HB_2BOB_2B和谷氨酸对神经母细胞瘤细胞的半数致死量。确定肌肽和高肌肽对这些毒性物质的剂量反应效应。方案4：用BMAA、HCO 3-、高肌肽和肌肽培养神经母细胞瘤细胞。假设4：来自微咸水和灰尘中蓝细菌的BMAA在具有较长CNDP 1基因型（LB 6 B，LB 7 B）和减少抗氧化剂二肽的军事人员中是有毒的。BMAA与碳酸氢盐相互作用形成多巴胺能毒素。目的4：研究这些抗氧化剂对BMAA和碳酸氢盐毒性的生物学相互作用。影响：横断面研究将确定GWI的遗传（CNDP 1等位基因）和蛋白质组学生物标志物。高肌肽、肌肽及其氨基酸的抗氧化和神经调节作用为我们的口服肌肽作为GWI治疗的双盲、安慰剂对照研究提供了理论基础。安全性和有效性问题将前瞻性地解决。神经母细胞瘤细胞将成为理解这些二肽和CNDP 1的功能、它们在保护免受氧化剂和谷氨酰胺介导的神经毒性中的作用以及蓝藻BMAA在GWI和ALS-PD发病机制中的潜在神经毒性作用的模型。