Sleep Disordered Breathing as a Targetable Risk Factor in Multiple Myeloma

睡眠呼吸障碍作为多发性骨髓瘤的目标危险因素

• 批准号: 10531893
• 负责人: MICHAEL H TOMASSON
• 金额: $ 57.25万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531893
• 关键词: Adult; American; Animals; Automobile Driving; Bone Marrow; Bone Marrow Neoplasms; Cells; Chemoresistance; Chronic; Clinical; Clinical Research; Clinical Trials; Continuous Positive Airway Pressure; DNA Sequence Alteration; Databases; Development; Diabetes Mellitus; Diagnosis; Disease; Disease remission; Dissection; Drug resistance; Engraftment; Epidemiology; Equipment and supply inventories; Exogenous Factors; Future; Gene Expression; Goals; Heart Diseases; Hematologic Neoplasms; Hematopoietic Neoplasms; Home; Hour; Human; Hypoxia; Hypoxia Pathway; Immunity; In complete remission; Infiltration; Inflammation; Light; Link; Literature; Macrophage; Malignant - descriptor; Malignant Neoplasms; Multiple Myeloma; Mus; Newly Diagnosed; Outcome; Oxygen; Patient-Focused Outcomes; Patients; Periodicity; Physiology; Plasma Cells; Population; Probability; Process; Progressive Disease; Quality of life; RNA; Recording of previous events; Relapse; Resistance; Risk Factors; Severities; Signal Pathway; Sleep; Sleep Apnea Syndromes; Soil; Stroke; Surface; Symptoms; Syndrome; Testing; Therapeutic; Time; Translating; Transplantation; Tumor Promotion; Tumor-associated macrophages; Work; cardiovascular disorder risk; case control; chemotherapy; design; experience; falls; genetic signature; human data; human subject; improved outcome; innovation; insight; mortality; pre-clinical; predictive marker; premalignant; public health relevance; response; screening; therapy resistant; transcriptome sequencing; treatment response; tumor

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.

抽象的 睡眠呼吸暂停是一种常见且诊断不足的综合症，影响至少4％的美国成年人和 与心脏病，中风，糖尿病和癌症死亡率有关。在睡眠呼吸暂停的患者中 动脉氧饱和度间歇性下降。循环发作通常随后是快速重新充氧。 该周期每小时发生60次，导致慢性间歇性缺氧（CIH），一种动态 与静态缺氧不同的生理学。我们的实验室正在开创研究CIH对骨骼的影响的研究 骨髓，免疫力和血液系统恶性肿瘤的发展，我们现在提出关键 将我们的工作转化为人类患者所需的研究。我们建议CIH会引起对 通过增加肿瘤相关巨噬细胞（TAMS）的抽象来增加化学疗法。在这个建议中，我们 目标：目标1：检验以下假设：夜间慢性间歇性缺氧的严重程度促进TAM Burnen AIM 2：测试连续正气道压力（CPAP）处理调节的假设 CD163+ CD206+巨噬细胞的抽象和基因表达，AIM 3：检验假设 慢性间歇性缺氧降低了新诊断的完全缓解的可能性 骨髓瘤。到项目期结束时，我们将确定CIH具有临床意义 对骨髓的影响，我们将在TAM的第一个深层表征上进行 CIH，我们将确定CIH严重程度与对的不良反应有关的程度 化学疗法。