Neural mechanisms by which chronic stress regulates inflammation in asthma

描述（由申请人提供）：哮喘是一种慢性炎症性疾病，是影响约13%美国成年人的重大公共卫生问题。哮喘患者患情绪或焦虑障碍的风险是无哮喘患者的两倍，这种合并症与哮喘控制较差、症状频率增加以及更多的医生和急诊室就诊有关。然而，旨在了解哮喘病理生理学和治疗的研究几乎完全忽视了大脑的作用。因此，本研究将探讨心理因素对哮喘相关生理影响的神经基础。这些项目的主要目标是：(1)阐明慢性社会心理压力影响哮喘炎症反应的神经回路；(2)量化慢性压力对肺功能和炎症的客观测量的影响；(3)评估通过正念训练积累的神经变化的影响，以改变慢性压力对气道炎症发展的影响。为了实现这些目标，将招募有或没有明显慢性生活压力的哮喘个体，以及有或没有慢性生活压力的健康非哮喘对照。所有参与者都将进行心理社会压力测试。正电子发射断层扫描（PET）将用于测量神经对应激源的反应，例如，在执行应激任务期间，放射性标记葡萄糖的摄取将发生。完成任务后收集的PET数据（葡萄糖代谢率）将反映任务执行过程中发生的相对神经活动。葡萄糖代谢率将与肺功能（FEV1）、炎症（痰和血嗜酸性粒细胞、呼出的一氧化氮）、免疫细胞对糖皮质激素抑制的敏感性、应激反应性（唾液皮质醇和α淀粉酶）、自我报告的哮喘症状控制和自我报告的心理因素（如抑郁和焦虑）相关。在高与低慢性应激哮喘患者和对照组的应激诱导糖代谢率的差异将被表征。此外，外周生理指标将被单独检查，并与葡萄糖代谢率的变化有关，以量化慢性应激对哮喘重要生理指标的影响。这些数据将为解决目标3的后续干预研究提供基础。正念冥想训练将被评估其影响慢性压力对哮喘症状表达的影响的能力。上述方案将在参与者接受正念训练之前使用，并在训练完成后再次使用，以检查神经对压力的反应可能发生的变化，这些变化是正念训练相关的潜在症状缓解的基础。候选人梅丽莎·罗森克兰茨博士的直接目标是了解慢性应激调节哮喘炎症过程的神经机制，以及哮喘的病理生理学促进情绪和焦虑障碍的神经机制。她的长期目标是推广这一目标；揭示心理事件导致疾病表现和进展的机制和途径，以及外周疾病表现导致认知和情绪变化的机制和途径。进一步说，梅丽莎希望为医疗保健和疾病管理的新方法做出贡献，在这些领域，大脑是重要的。梅丽莎是独一无二的，能够成功地进行拟议的研究并实现这些目标。她已经展示了她执行这种性质的高度复杂和合作研究项目的能力，这在她强大的出版记录中是显而易见的。然而，跨学科研究对年轻科学家提出了重大挑战。要以最严格的方式追求这些目标，需要至少三个不同方法论领域的专业知识：心理学、神经科学和免疫学。通常，一个学生要花几年时间才能成为其中任何一个领域的专家。到目前为止，她的训练主要集中在前两个方面。职业发展奖将为Melissa提供受保护的时间、资源和正式的结构，通过正式的指导和咨询关系，极大地扩展她在免疫学和神经解剖学方面的专业知识，并为她的工具库增加新的神经成像模式（PET）。此外，她将接受长期目标关键部分的培训和支持：通过心理训练技术确定神经功能的变化如何影响心理事件与疾病表现之间的关系。Melissa的赞助人Richard Davidson博士和共同赞助人William Busse博士提供了无与伦比的专业知识、培训机会和资源，使Melissa能够在解决重大公共卫生问题方面蓬勃发展，成为一名年轻的研究者。她的问题易于处理，她的研究再提交和培训目标大胆而创新。她为这个机会带来的专业知识，以及她的导师和顾问团队可以传授给她的专业知识和资源，为梅丽莎在这个领域做出重大贡献创造了一个理想的场景。

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease that poses a significant public health problem affecting approximately 13% of U.S. adults. Individuals with asthma have a two-fold higher risk of developing a mood or anxiety disorder than those without asthma and this co-morbidity is associated with poorer asthma control, increased symptom frequency, and more physician and emergency room visits. Yet research directed at understanding asthma pathophysiology and treatment has neglected the role of the brain almost entirely. The proposed research, therefore, will examine the neural underpinnings of the influence of psychological factors on asthma-relevant physiology. The primary objectives of these projects are to (1) elucidate the neural circuitry through which chronic psychosocial stress influences the inflammatory response in asthma (2) quantify the impact of chronic stress on objective measures of lung function and inflammation and (3) evaluate the impact of neural changes, accrued through training in mindfulness, to alter the impact of chronic stress on the development of airway inflammation. To accomplish these objectives, asthmatic individuals with and without significant chronic life stress, as well as healthy non-asthmatic controls with and without chronic life stress, will be recruited for study. All participants will perform a psychosocial stress test. Positron emission tomography (PET) will be used to measure the neural response to the stressor, such that uptake of radiolabeled glucose will take place during performance of the stress task. PET data (glucose metabolic rate) collected after completion of the task will reflect the relative neural activity that occurred during task performance. Glucose metabolic rate will be examined in relation to measures of lung function (FEV1), inflammation (sputum and blood eosinophils, exhaled nitric oxide), sensitivity of immune cells to inhibition by glucocorticoids, stress responsivity (salivary cortisol and alpha amylase), self-reported asthma symptom control, and self-reported psychological factors (e.g. depression and anxiety). Differences in stress-induced glucose metabolic rate in high versus low chronically stressed asthmatics and controls will be characterized. In addition, the peripheral physiological measures will be examined on their own, and in relation to changes in glucose metabolic rate, to quantify the impact of chronic stress on physiological measures of import to asthma. These data will provide the basis for a subsequent intervention study that addresses objective 3. Training in mindfulness meditation will be evaluated for its ability to impact the effects of chronic stress on the factors that underlie asthma symptom expression. The protocol described above will be employed before participants receive mindfulness training and again following completion of training, in order to examine changes that may occur in the neural response to stress that underlie potential symptom alleviation associated with mindfulness training. The immediate goal of the candidate, Dr. Melissa Rosenkranz, is to understand the neural mechanisms through which chronic stress regulates inflammatory processes in asthma and through which the pathophysiology of asthma promotes mood and anxiety disorders. Her long-term goal is to generalize this aim; to bring to light the mechanisms and pathways through which mental events lead to disease expression and progression, and through which peripheral disease expression causes cognitive and emotional changes. By extension, Melissa hopes to contribute to new ways of approaching healthcare and management of disease, where the brain is featured prominently. Melissa is uniquely situated to successfully carry out the proposed research and to realize these goals. She has already demonstrated her ability to execute highly complex and collaborative research projects of this nature, as is evident in her strong publication record. Nonetheless, interdisciplinary research poses a significant challenge to young scientists. To pursue these goals with the utmost rigor requires expertise in not one, but at least three distinct methodological domains: psychology, neuroscience, and immunology. Typically, a student would spend several years becoming an expert in any one of these domains. Thus far, her training has focused primarily on methods in the first two. A career development award will provide the protected time, resources, and formal structure for Melissa to greatly expand her expertise in immunology and neuroanatomy via formal mentorship and advisory relationships, and to add a new neuroimaging modality (PET) to her repertoire of tools. In addition, she will receive training in and support for a key component of her long-term goal: to determine how changing neural function, through mental training techniques, impacts the relationship between psychological events and disease expression. Melissa's sponsor, Dr. Richard Davidson, and co-sponsor, Dr. William Busse offer unparalleled expertise, training opportunities, and resources with which Melissa can flourish as a young investigator in addressing questions of significant public health importance. Her questions are tractable and her research resubmission and training objectives are bold and innovative. The combination of expertise that she brings to this opportunity and the expertise and resources that her team of mentors and advisors can impart to her creates an ideal scenario for Melissa to make substantial contributions to this field.