Neural mechanisms by which chronic stress regulates inflammation in asthma

慢性应激调节哮喘炎症的神经机制

• 批准号: 8725582
• 负责人: MELISSA A ROSENKRANZ
• 金额: $ 9.82万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725582
• 关键词: Accident and Emergency department; Acute; Address; Adult; Affect; American Medical Association; Anterior; Anxiety; Anxiety Disorders; Asthma; Attention; Award; Biological; Biological Assay; Blood; Brain; Brain Diseases; Cells; Chronic; Chronic Disease; Chronic stress; Cognitive; Communication; Comorbidity; Complex; Control Groups; Data; Deoxyglucose; Depressive disorder; Deterioration; Development; Diabetes Mellitus; Disease; Disease Management; Education; Emotional; Emotions; Event; Exhalation; Extrinsic asthma; Frequencies; Functional disorder; Glucocorticoids; Glucose; Goals; Healthcare; Hydrocortisone; Image; Immune; Immune system; Immunology; Impairment; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Instruction; Insula of Reil; Interdisciplinary Study; Intervention; Intervention Studies; Journals; K-Series Research Career Programs; Lead; Leadership; Life; Life Stress; Lung Inflammation; Measurement; Measures; Medical; Meditation; Melissa; Mental Depression; Mentors; Mentorship; Metabolic; Methodology; Methods; Mind; Modality; Modeling; Molecular; Mood Disorders; Moods; Morbidity - disease rate; National Center for Complementary and Alternative Medicine; Nature; Neuroanatomy; Neurophysiology - biologic function; Neurosciences; Nitric Oxide; Organ; Outcome; Outcome Measure; Participant; Pathway interactions; Patient Self-Report; Performance; Peripheral; Physicians; Physics; Physiological; Physiology; Pneumonia; Positron-Emission Tomography; Posture; Process; Protocols documentation; Psyche structure; Psychological Factors; Psychology; Psychosocial Stress; Public Health; Publications; Pulmonary Function Test/Forced Expiratory Volume 1; Radiolabeled; Recruitment Activity; Relative (related person); Reporting; Research; Research Institute; Research Personnel; Research Project Grants; Research Proposals; Resources; Respiratory physiology; Role; Salivary; Scientist; Services; Social Interaction; Spirometry; Sputum; Stimulus; Stress; Stress Tests; Stressful Event; Structure; Students; Symptoms; Task Performances; Techniques; Time; Training; Training Technics; Trier Social Stress Test; Visit; Walking; Work; Yoga; acute stress; airway inflammation; alpha-amylase; base; biological adaptation to stress; bodily sensation; career development; cingulate cortex; cost; design; eosinophil; experience; high risk; indexing; inflammatory marker; innovation; instructor; lung imaging; meetings; mental training; mindfulness; mindfulness meditation; mindfulness-based stress reduction; neglect; neural circuit; neuroimaging; neuromechanism; operation; programs; psychologic; psychosocial; radiotracer; relating to nervous system; response; stressor; tool; uptake

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.

描述(申请人提供)：哮喘是一种慢性炎症性疾病，对大约13%的美国成年人造成严重的公共卫生问题。患有哮喘的人患情绪或焦虑症的风险是没有哮喘的人的两倍，这种共同发病率与哮喘控制较差、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，这项拟议的研究将检验心理因素对哮喘相关生理学影响的神经基础。这些项目的主要目标是(1)阐明慢性心理社会应激影响哮喘炎症反应的神经回路；(2)量化慢性应激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，以改变慢性应激对呼吸道炎症发展的影响。为了实现这些目标，将招募有和没有明显慢性生活压力的哮喘患者以及有和没有慢性生活压力的健康非哮喘对照组进行研究。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)将被用来测量神经对应激源的反应，以便在执行应激任务期间摄取放射性标记的葡萄糖。任务完成后收集的PET数据(葡萄糖代谢率)将反映任务执行期间发生的相对神经活动。葡萄糖代谢率将根据肺功能(FEV1)、炎症(痰和血中嗜酸性粒细胞、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(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)进行检查。应激诱导的葡萄糖代谢率在高和低慢性应激哮喘患者和对照组之间的差异将被表征。此外，将单独检查外周生理指标，并与葡萄糖代谢率的变化相关，以量化慢性应激对输入哮喘的生理指标的影响。这些数据将为后续针对目标3的干预研究提供基础。正念冥想训练将评估其影响慢性应激对哮喘症状表达基础因素的影响的能力。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，这是与正念训练相关的潜在症状缓解的基础。候选人梅丽莎·罗森克兰兹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。她的长期目标是概括这一目标；揭示心理事件导致疾病表达和进展的机制和途径，以及外围疾病表达引起认知和情感变化的机制和途径。通过延伸，梅丽莎希望为处理医疗保健和疾病管理的新方法做出贡献，在这些方法中，大脑是突出的特征。梅丽莎是成功开展拟议研究并实现这些目标的得天独厚的人选。她已经证明了她有能力执行这种性质的高度复杂和合作的研究项目，这从她出色的出版记录中可见一斑。尽管如此，跨学科研究对年轻科学家构成了巨大的挑战。要最严格地追求这些目标，需要的不是一个，而是至少三个不同的方法论领域的专业知识：心理学、神经科学和免疫学。通常情况下，一个学生会花几年时间成为这些领域中的任何一个领域的专家。到目前为止，她的培训主要集中在前两种方法上。职业发展奖将为梅丽莎提供受保护的时间、资源和正式结构，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，并为她的工具库添加新的神经成像设备(PET)。此外，她将接受长期目标的一个关键组成部分的培训和支持：确定通过心理训练技术改变神经功能如何影响心理事件和疾病表现之间的关系。梅丽莎的赞助人理查德·戴维森博士和共同赞助人威廉·巴斯博士提供了无与伦比的专业知识、培训机会和资源，使梅丽莎作为一名年轻的研究人员能够在解决重大公共卫生问题方面取得成功。她的问题很容易处理，她的研究重新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与她的导师和顾问团队可以传授给她的专业知识和资源相结合，为梅丽莎为这一领域做出实质性贡献创造了一个理想的场景。