Morphine Actions on the Immune System

描述(由申请人提供)： 申请K02独立科学家奖是为了让我有更多的时间从事我的研究项目和其他与研究相关的活动，并进一步发展我在药物滥用的神经免疫学领域的研究事业。我研究的主要目标是确定滥用药物，如吗啡，对免疫反应及其进展的影响。我们先前已经报道，在体内，长期暴露于吗啡可以抑制下丘脑-垂体-肾上腺(HPA)轴，其机制是通过脱敏IL-1β(IL-1β)诱导的下丘脑室旁核(参与HPA轴激活的大脑区域)的神经元激活，从而抑制IL-1β诱导的下丘脑促肾上腺皮质激素释放因子mRNA的转录，并减少肾上腺产生抗炎物质，如皮质酮。相反，我们发现吗啡增强了IL-1β诱导的免疫反应，如肠系膜小静脉中的白细胞-内皮黏附(LEA)。因此，慢性吗啡暴露可以通过破坏IL-1介导的局部炎症反应(如LEA)和HPA轴的抗炎效应之间的平衡来促进潜在的破坏性炎症反应。最近，我的R01资助金(DA07058-12)被续期5年(3/15/02-1/31/07)，我的R01资助金(DA07058-12)被续期5年(3/15/02-1/31/07)，我还获得了新泽西州高等教育委员会授予的设备资助金，用于购买序列检测系统、荧光成像仪和荧光平板阅读器。我的R01项目中的研究旨在扩展我们之前的发现，以确定吗啡影响细菌感染进展的机制。其具体目的是确定细菌内毒素调节MU阿片受体(MOR)依赖通路的分子和细胞过程，以及这种调节如何与内毒素休克的进展相关。这一K02奖项将使我能够将最大的时间用于：1)致力于我的研究项目的目标，2)获得使用最先进的方法的经验，包括实时聚合酶链式反应、基于荧光的生物分析和微阵列技术，3)指导研究型学生和初级研究人员，以及4)为我的实验室员工和学生建立负责任的研究进行中的正式培训计划。

DESCRIPTION (provided by applicant): This application for a K02 Independent Scientist Award is submitted to enable me to devote additional time to my research projects and other research-related activities and to further my research career in the field of neuroimmunology of drug abuse. The primary goal of my research is to define the influence of drugs of abuse, such as morphine, on immune responses and their progression. We have previously reported that chronic exposure to morphine suppresses the hypothalamic-pituitary-adrenal (HPA) axis in vivo by desensitizing interleukin-1beta (IL-1beta)-induced neuronal activation of the hypothalamic paraventricular nucleus, an area of the brain involved in the activation of the HPA axis, thus, inhibiting IL-1beta-induced transcription of corticotropin releasing factor mRNA by the hypothalamus and decreasing the production of anti-inflammatory agents, such as corticosterone, by the adrenal gland. Conversely, we have found that morphine potentiates IL-1beta-induced immune responses, such as leukocyte-endothelial adhesion (LEA), in mesenteric venules. Thus, it appears that chronic morphine exposure can promote a potentially damaging inflammatory reaction by disrupting the balance between IL-1?-mediated local inflammatory responses, such as LEA, and the anti-inflammatory effects of the HPA axis. Recently, my R01 grant (DA07058-12) entitled, "Morphine actions on the immune system", was renewed for an additional five years (3/15/02-1/31/07), and I was also awarded an equipment grant by the New Jersey Commission on Higher Education to purchase a sequence detection system, a fluorescent imager, and a fluorescent plate reader. The studies in my R01 project are designed to extend our previous findings to define the mechanisms by which morphine influences the progression of bacterial infection. The Specific Aims are to define the molecular and cellular processes by which bacterial endotoxins modulate mu opioid receptor (MOR)-dependent pathways and how such modulation is related to the progression of endotoxin shock. This K02 award will enable me to devote maximum time to: 1) working on the aims of my research projects, 2) gaining experience in the use of state-of-the-art methodologies, including real time PCR, fluorescence-based biological assays, and microarray technology, 3) mentoring research students and junior researchers, and 4) establishing an ongoing formal training program in the responsible conduct of research for my lab staff and students.