Mentoring Research in the Physiology of Sleep Disordered Breathing

描述（由申请人提供）：该提案将为Ayappa博士提供受保护的时间和支持，同时她(1)指导研究生，博士后研究员和初级教师从事睡眠障碍患者导向研究；(2)对睡眠呼吸障碍（SDB）患者进行临床研究；(3)增强以患者为导向的研究和指导能力。Ayappa博士积极参与SDB生理学、诊断、治疗和结果方面的研究，为指导提供了研究机会。阻塞性睡眠呼吸暂停（OSA）是一种非常普遍的疾病，估计影响了15%的美国人口。未经治疗的OSA有显著的发病率和死亡率，包括心血管和神经认知障碍。提出了多个研究方向。第一个项目（1U01OH010415-01）通过对世贸中心急救人员中高患病率的鼻部不适和OSA并存的情况，研究鼻腔病理在OSA发展中的作用及其对CPAP依从性的影响。具体目的是：(i)在1000名没有证据表明9/11前OSA的受试者中，检查9/11后OSA（使用家庭睡眠监测）与上呼吸道疾病之间的关系（ii）确定9/11后OSA、上呼吸道疾病、鼻腔炎症（白细胞计数和可溶性IL-8、IL-6、IL-8、IL-6）之间的关系。（iii）将OSA患者的鼻腔阻力与CPAP依从性联系起来，表明使用capflex降低呼气压将改善CPAP依从性。第二个项目（候选人之前的r01, 2013年2月更新修订）的目标是了解SDB与OSA患者日间功能之间的关系（或缺乏关系的原因）。虽然大多数OSA患者报告白天嗜睡过度（EDS），但SDB与嗜睡的相关性较差。越来越清楚的是，个体易感性等因素可能导致个体患者对SDB应激反应的差异。具体目的是证明控制次优CPAP（标准剂量的SDB）后发生的EDS水平与24小时睡眠剥夺后发生的EDS水平之间的相关性。假设是，对这两种不同形式的睡眠中断的易感性是相关的，并定义了一个人的“特质”。这项工作的延伸是第三个合作项目（目前资助试点），该项目在一组老年受试者中研究SDB和阿尔茨海默病（AD）生物标志物之间的关系。该研究探讨了老年痴呆症是否会导致SDB，或者SDB是否会促进神经退行性变。提案中概述的活动对科学和公共卫生都有影响。根据国家睡眠障碍研究中心的记录，这项指导工作将解决睡眠障碍研究人员严重短缺的问题。这项实验工作对了解SDB的生理学及其预后、诊断和治疗具有重要意义，对改善数百万睡眠呼吸暂停患者的健康和生活质量具有潜在意义。

DESCRIPTION (provided by applicant): This proposal will provide protected time and support to Dr. Ayappa while she (1) mentors graduate students, post-doctoral fellows and junior faculty pursuing careers in patient-oriented research in sleep disorders; (2) conducts clinical research in patients with sleep disordered breathing (SDB) and (3) augments her capabilities to conduct patient-oriented research and mentoring. Dr. Ayappa is actively involved in research in physiology, diagnosis, treatment and outcomes of SDB that provides research opportunities for mentoring. Obstructive sleep apnea (OSA) is a highly prevalent disorder estimated to affect 15% of the US population. Untreated OSA has significant morbidity and mortality including cardiovascular and neurocognitive impairment. Multiple directions are proposed for the research. The first project (1U01OH010415-01) uses the coexistence of the high prevalence of nasal complaints and OSA in World Trade Center responders to examine the role of nasal pathology in the development of OSA and its impact on CPAP adherence. The Specific aims are to (i) Examine the relationships between post-9/11 OSA (using home sleep monitoring) and upper airway disease, in 1000 subjects without evidence of pre-9/11OSA (ii) Determine the relationship between post-9/11 OSA, upper airway disease, nasal inflammation (leukocyte counts and soluble IL-8, IL-6, TNF¿) and nasal resistance (rhinomanometry) (iii) Relate nasal resistance to CPAP adherence in patients with OSA to show that reduction of expiratory pressure using CPAPFlex will improve CPAP adherence. The goal of the second project (candidate's prior R01with renewal revision Feb 2013) is to understand the relationship (or reasons for lack thereof) between SDB and daytime function in OSA patients. Although majority of patients with OSA report excessive daytime sleepiness (EDS), the correlation between measures of SDB and sleepiness is poor. It is increasingly clear that factors such as individual susceptibility may contribute to differences in how individual patients respond to the stress of SDB. The specific aim is to demonstrate a correlation between the level of EDS that develops after controlled suboptimal CPAP (a standardized dose of SDB) and the level of EDS after 24 hours of sleep deprivation. The hypothesis is that susceptibility to these two different forms of sleep disruption is correlated and defines a "trait" for an individual. An extension of this work i a third collaborative project (currently funded pilots) that examines the relationship between SDB and Alzheimer's Disease (AD) biomarkers in a cohort of elderly subjects. The study examines whether AD causes SDB in the elderly, or if SDB acts as a factor promoting neurodegeneration. The activities outlined in the proposal have implications for science and public health. The mentoring work will address a critical shortage of researchers in sleep disorders as documented by the National Center on Sleep Disorders. The experimental work is relevant for understanding the physiology of SDB and its outcomes, its diagnosis and treatment with potential for improving health and quality of life in millions of patients who suffer from sleep apnea.