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: 7952576
• 负责人: MELISSA A ROSENKRANZ
• 金额: $ 9.03万
• 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/7952576
• 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; Light; Measurement; Measures; Medical; Meditation; Melissa; Mental Depression; Mentors; Mentorship; Metabolic; Methodology; Methods; Mind; Modality; Modeling; Molecular; 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; mindfulness; mindfulness meditation; mindfulness-based stress reduction; neglect; neural circuit; neuroimaging; neuromechanism; operation; programs; psychologic; psychosocial; public health relevance; 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. PUBLIC HEALTH RELEVANCE: Asthma is a chronic disease that affects nearly 13% of adults in the U.S., causing substantial impairment that is reflected in the tens of millions of missed days of work, and doctors' and emergency room visits it leads to annually. Those who have asthma are twice as likely to develop depression and anxiety, which are associated with more frequent and severe asthma symptoms, especially in those under chronic stress. The project proposed here seeks to understand the role of the brain in these associations and to evaluate the neural mechanisms through which a safe, low-cost intervention, that influences the function of body via the mind, may diminish the expression of asthma symptoms.

描述（由申请人提供）：哮喘是一种慢性炎症性疾病，造成严重的公共卫生问题，影响约 13% 的美国成年人。患有哮喘的人患情绪或焦虑障碍的风险比没有哮喘的人高两倍，这种共病与哮喘控制较差、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，拟议的研究将检查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）阐明慢性心理社会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客观指标的影响，以及（3）评估通过正念训练产生的神经变化的影响，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，将招募有或没有显着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者进行研究。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）将用于测量神经对应激源的反应，以便在执行应激任务期间吸收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）将反映任务执行过程中发生的相对神经活动。将检查葡萄糖代谢率与肺功能（FEV1）、炎症（痰液和血液嗜酸性粒细胞、呼出一氧化氮）、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以及自我报告的心理因素（例如抑郁症和抑郁症）等指标的关系。 焦虑）。将描述高压力与低压力慢性压力哮喘患者和对照组中压力诱导的葡萄糖代谢率的差异。此外，将单独检查外周生理测量，并与葡萄糖代谢率的变化相关，以量化慢性压力对哮喘的生理测量的影响。这些数据将为后续针对目标 3 的干预研究提供基础。将评估正念冥想训练对慢性压力对哮喘症状表现背后因素的影响的能力。上述协议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，以便检查神经对压力的反应可能发生的变化，而压力是与正念训练相关的潜在症状缓解的基础。 候选人 Melissa Rosenkranz 博士的近期目标是了解慢性压力调节哮喘炎症过程以及哮喘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； 揭示精神事件导致疾病表达和进展的机制和途径，以及周围疾病表达引起认知和情绪变化的机制和途径。除此之外，梅丽莎希望为医疗保健和疾病管理的新方法做出贡献，其中大脑在这方面尤为突出。 梅丽莎具有独特的优势，能够成功开展拟议的研究并实现这些目标。 她已经展示了执行此类性质的高度复杂和协作研究项目的能力，这一点从她出色的发表记录中可以看出。尽管如此，跨学科研究对年轻科学家提出了重大挑战。要以最严格的要求追求这些目标，需要的不是一个领域的专业知识，而是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，学生需要花费几年的时间才能成为这些领域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，并在她的工具库中添加新的神经影像模式 (PET)。此外，她还将接受其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。 梅丽莎的资助者理查德·戴维森博士和共同资助者威廉·布斯博士提供了无与伦比的专业知识、培训机会和资源，使梅丽莎能够作为一名年轻的研究者在解决具有重大公共卫生重要性的问题上蓬勃发展。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相结合，为梅丽莎在这一领域做出重大贡献创造了理想的场景。 公共卫生相关性：哮喘是一种慢性疾病，影响着美国近 13% 的成年人，造成严重损害，这反映在每年因哮喘导致数千万天的缺勤、医生和急诊室就诊。患有哮喘的人患抑郁症和焦虑症的可能性是其他人的两倍，这与更频繁和更严重的哮喘症状有关，特别是对于那些处于长期压力下的人。这里提出的项目旨在了解大脑在这些关联中的作用，并评估神经机制，通过这种机制，安全、低成本的干预措施可以通过思想影响身体功能，从而减少哮喘症状的表现。