GPR109A and Parkinson's Disease: Role of Niacin in Outcome Measures

 描述（由申请人提供）： 我们很高兴地观察到帕金森病（PD）患者和对照个体的白色血细胞（巨噬细胞）中GPR 109 A水平的显著差异。此外，我们观察到与PD患者和年龄匹配的对照组的小胶质细胞共定位的黑质区域中GPR 109 A表达的相似变化。我们是第一个发现这些变化的实验室。烟酸是一种抗炎剂，已知它通过GPR 109 A和核因子-B（NFk B）途径阻止炎症。 已知烟酸阻断NF κ B向细胞核的易位，从而减少促炎细胞因子的产生。我们将通过分析PD患者脑脊液（CSF）中的炎性细胞因子来研究烟酸在PD患者中的这些作用。据记载，接受卡比多巴治疗的PD患者的烟酸水平降低。我们发现与年龄匹配的对照组相比，PD患者的烟酸指数（NAD/NADP比率）显著降低，表明NAD水平降低和氧化应激增加。我们提出了一个新的假设，即通过减少炎症，烟酸治疗将恢复烟酸水平沿着GPR 109 A水平，并将有助于改善PD患者的运动协调和认知表现。具体目标：本提案的两个具体目标如下：目标1A：确定烟酸补充是否会改善与运动协调和认知测试表现相关的PD患者的症状。目的1 B：确定PD患者中GPR 109 A的上调是否将响应于烟酸治疗以减少CSF中的炎性标志物。目的2：在体外模型中研究GPR 109 A作为抗炎治疗靶点的分子机制。

 DESCRIPTION (provided by applicant): Project Summary/Abstract We are excited to observe significant differences in the GPR109A levels in the white blood cells (macrophages) of Parkinson's disease (PD) patients and control individuals. Moreover, we observed similar changes in the GPR109A expressions in the substantia nigra regions that co-localize with the microglia of the PD patients and age-matched controls. We are the first lab to denote these changes. GPR109A is an anti- inflammatory receptor and niacin acts on it. Niacin is an anti-inflammatory agent and it is known to halt inflammation via GPR109A and nuclear factor-¿B (NFkB) pathway. Niacin is known to block the translocation of NFKB to nucleus and thus reduce the production of pro-inflammatory cytokines. We will study these effects of niacin in PD patients by analyzing inflammatory cytokines in the cerebrospinal fluid (CSF) of PD patients. It has been documented that PD patients who are on carbidopa treatment have decreased levels of niacin. We have found significant reduction in the niacin index (NAD/NADP ratio) in PD patients compared to age- matched controls, denoting reduced NAD levels and increased oxidative stress. We propose a novel hypothesis that by reducing inflammation, niacin treatment will restore niacin levels along with GPR109A levels and will help improve motor coordination and cognition performances in the PD patients. Specific Aims: The two specific aims of the current proposal are as follows: Aim 1 A: To determine whether niacin supplementation will improve the symptoms of PD patients as correlated by performances in motor coordination and cognitive tests. Aim 1 B: To determine whether up-regulation of GPR109A in PD patients will respond to niacin therapy in reducing inflammatory markers in the CSF. Aim 2: To study the molecular mechanisms related to GPR109A as an anti-inflammatory therapeutic target in in-vitro models.