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

 描述(由申请人提供)： 项目摘要/摘要我们很高兴地观察到帕金森氏病(PD)患者和对照组白细胞(巨噬细胞)中Gpr109a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同定位的黑质区域中Gpr109a表达的类似变化。我们是第一个表示这些变化的实验室。Gpr109a是一种抗炎受体，烟酸对其有作用。烟酸是一种抗炎药，已知通过Gpr109a和核因子B(NFkB)途径抑制炎症。众所周知，烟酸可以阻止NFKB转位到细胞核，从而减少促炎细胞因子的产生。我们将通过分析PD患者脑脊液中的炎性细胞因子来研究烟酸在PD患者中的这些作用。已有文献证明，接受卡比多巴治疗的帕金森病患者的烟酸水平有所降低。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，氧化应激增加。我们提出了一个新的假设，即通过减轻炎症，烟酸治疗将恢复烟酸水平和Gpr109a水平，并有助于改善PD患者的运动协调和认知能力。具体目的：本提案的两个具体目的如下：目的1A：确定补充烟酸是否会改善帕金森病患者的症状，并与运动协调和认知测试的表现相关联。目的1B：探讨烟酸治疗对帕金森病患者脑脊液中炎症标志物的影响。目的：通过体外模型研究Gpr109a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.