Sleep Disordered Breathing as a Targetable Risk Factor in Multiple Myeloma

摘要 睡眠呼吸暂停是一种常见的和未被诊断的综合征，影响至少4%的美国成年人， 与心脏病、中风、糖尿病和癌症死亡率有关。在睡眠呼吸暂停患者中， 动脉血氧饱和度间歇性地福尔斯下降。周期性发作之后通常是快速复氧。 这种循环每小时发生60次，导致慢性间歇性缺氧（CIH），这是一种动态的缺氧。 不同于静态缺氧的生理学。我们的实验室是CIH对骨骼影响研究的先驱 骨髓，免疫和血液恶性肿瘤的发展，我们现在提出关键的 将我们的研究成果转化为人类患者所需的研究。我们认为CIH可以引起耐药性， 通过增加肿瘤相关巨噬细胞（TAM）的丰度来增加化疗。在本提案中，我们 目的：目的1：验证夜间慢性间歇性缺氧严重程度促进TAMs的假设 目的2：检验持续气道正压通气（CPAP）治疗调节 CD163+ CD206+巨噬细胞的丰度和基因表达，目的3：检验假设 慢性间歇性缺氧降低了新诊断的 骨髓瘤到项目期结束时，我们将确定CIH具有临床意义， 在对骨髓的影响，我们将进行第一次深入表征的TAM的背景下， CIH，我们将确定CIH的严重程度与对以下疾病的不良反应有关： 化疗

ABSTRACT Sleep apnea is a common and underdiagnosed syndrome that impacts at least 4% of American adults and is associated with heart disease, stroke, diabetes, and cancer mortality. In patients with sleep apnea, arterial oxygen saturation intermittently falls. Cyclic episodes are typically followed by rapid re-oxygenation. This cycle occurs as often as 60 times per hour, resulting in chronic intermittent hypoxia (CIH), a dynamic physiology that is distinct from static hypoxia. Our lab is pioneering the study of CIH’s effects on the bone marrow, immunity, and the development of hematological malignancies and we now propose the critical studies necessary to translate our work to human patients. We propose that CIH can cause resistance to chemotherapy by increasing the abundance of tumor-associated macrophages (TAMs). In this proposal, we aim: Aim 1: Test the hypothesis that severity of nighttime chronic intermittent hypoxia promotes TAMs burden Aim 2: Test the hypothesis that continuous positive airway pressure (CPAP) treatment modulates the abundance and gene expression of CD163+ CD206+ macrophages, and Aim 3: Test the hypothesis that chronic intermittent hypoxia decreases the probability of complete remission in newly diagnosed myeloma. By the end of the project period, we will have established that CIH has a clinically meaningful impact on the bone marrow, we will have performed the first deep characterization of TAMs in the context of CIH, and we will have determined the degree to which CIH severity is linked to poor response to chemotherapy.