Molecular effects of mind-body intervention on GC sensitivity and immune function

描述(由申请人提供)：这是为加州大学旧金山分校博士后杰弗里·米卢什博士申请K01奖项。米卢什博士正在确立自己作为一名年轻研究员的地位，他正在研究替代医学干预措施重置免疫系统神经内分泌调节的能力。这一K01奖项将为米卢什博士提供必要的支持，以实现以下目标：(1)成为免疫功能神经内分泌调节的分子和流式细胞术分析专家；(2)调查身心干预对免疫细胞功能的影响；(3)将生物统计学方法应用于临床研究；以及(4)开发独立研究所需的资源。为了实现这些目标，米卢什博士组建了一个指导团队，成员包括主要导师、实验医学部副主任道格拉斯·尼克松博士(其实验室研究免疫细胞对压力和一系列病原体的反应)和三名共同导师：医学教授、加州大学欧舍综合医学中心研究主任、NCCAM资助的两项心身干预研究的联席首席研究员Frederick Hecht博士；具有临床试验经验的心理神经免疫学和实验室压力范式专家Margaret Kemeny博士；以及当前最先进的临床研究生物统计分析专家Peter Bacchetti博士。委员会成员将定期与米卢什博士会面，讨论结果、进展、潜在问题和未来方向。此外，精心挑选了教学课程、讲座和研究会议，为米卢什博士提供额外的培训，帮助他转变为一名完全独立的研究人员。该项目的目标是通过改进和验证用于评估糖皮质激素受体表达和功能的新的流式细胞仪分析，更详细地了解神经内分泌调节免疫反应的机制(目标1)。然后，这些新的检测方法将被用于确定体内皮质醇水平是否与免疫细胞中糖皮质激素受体的表达相关(目标2)。最后，这些新的基于流式细胞术的分析将被用来理解精神-身体干预如何‘重置’神经内分泌和免疫系统之间的这种重要的双向交流(目标3)。这项研究将为更大范围、更全面地调查心身干预改变神经内分泌信号和免疫系统功能的机制奠定基础，在K奖金期结束前申请R01奖金。公共卫生相关性：更全面地了解神经内分泌对免疫细胞功能的控制，对于理解心身干预通过调节神经内分泌信号影响免疫功能的分子机制非常重要。 与公共健康相关：冥想和瑜伽等身心干预措施可能会对免疫系统产生重要影响，部分原因是这些干预措施对应激激素信号通路的影响。然而，我们对这些干预措施对免疫系统的潜在影响的了解是有限的，因为我们对这些干预措施可能实现的应激激素水平的变化实际上如何影响免疫系统的了解存在差距。这项应用的长期目标是开发必要的新分析方法，以研究应激激素控制免疫细胞功能的机制，以及身心干预如何重新设置这一沟通途径。

DESCRIPTION (provided by applicant): This is an application for a K01 award for Dr. Jeffrey Milush, a post-doctoral fellow at the University of California, San Francisco. Dr. Milush is establishing himself as a young investigator researching the ability of alternative medical interventions to reset neuroendocrine regulation of the immune system. This K01 award will provide Dr. Milush with the support necessary to accomplish the following goals: (1) to become an expert in molecular and flow cytometric analyses of neuroendocrine modulation of immune function; (2) to conduct investigations of the affects of mind-body interventions on immune cell function; (3) to implement biostatistical methods in clinical studies; and (4) to develop the resources necessary for an independent research career. To achieve these goals, Dr. Milush has assembled a mentoring team comprised of a primary mentor, Dr. Douglas Nixon, Associate Chief of the Division of Experimental Medicine, whose laboratory studies immune cell responses to stress and an array of pathogens, and three co-mentors: Dr. Frederick Hecht, Professor of Medicine, Research Director of the UCSF Osher Center for Integrative Medicine, and co-Principal Investigator on the two NCCAM-funded mind-body intervention studies; Dr. Margaret Kemeny, an expert in psychoneuroimmunology and laboratory stress paradigms with experience in clinical trials; and Dr. Peter Bacchetti, an expert in current state-of-the-art biostatistical analysis of clinical studies. Committee members will meet with Dr. Milush regularly to discuss results, progress, potential problems, and future directions. Furthermore, didactic courses, lectures, and research conferences have been carefully selected to provide Dr. Milush with additional training that will facilitate his transition to a completely independent investigator. The goal of this project is to develop a more detailed mechanistic understanding of neuroendocrine regulation of immune responses through the refinement and validation of novel flow cytometric assays for the assessment of glucocorticoid receptor expression and function (Aim 1). The novel assays will then be used to determine whether in vivo cortisol levels correlate with glucocorticoid receptor expression in immune cells (Aim 2). Lastly, these novel flow cytometry-based assays will be used to understand how mind-body interventions might 'reset' this important bi-directional communication between the neuroendocrine and immune system (Aim 3). This research will form the basis for a larger, more comprehensive investigation of the mechanisms by which mind-body intervention changes neuroendocrine signaling and immune system function in an R01 grant application before the end of the K award period. Public health relevance: A more complete understanding of neuroendocrine control of immune cell function is important for understanding the molecular mechanisms by which mind-body interventions affect immune function through modulation of neuroendocrine signaling. PUBLIC HEALTH RELEVANCE: Mind-body interventions, such as meditation and yoga, may have important effects on the immune system in part through the effects of these interventions on stress hormone signaling pathways. Our understanding of the potential effects of these interventions on the immune system is limited however, by gaps in our knowledge of how changes in stress hormone levels potentially achieved by these interventions actually affect the immune system. The long-term goal of this application is to develop new assays necessary to study the mechanisms by which stress hormones control immune cell function and how mind-body interventions 'reset' this communication pathway.