NIGHTTIME HYPOXEMIA IN TEENAGERS WITH ATAXIA TELANGIECTASIA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 青少年和青壮年共济失调毛细血管扩张症患者的夜间低氧血症和炎症 摘要 共济失调毛细血管扩张症(A-T)是一种在共济失调毛细血管扩张症基因(ATM)突变的人中发现的遗传性疾病。ATM基因在双链(DS)DNA断裂时被激活。患有A-T的人对氧化应激的有害影响特别敏感。这些应激包括暴露于电离辐射(IR)和缺氧/复氧损伤等。ATM中的缺陷细胞在暴露于氧化应激时可能死亡或衰老，从而改变损伤反应，损害恢复。A-T与频繁的肺部恶化有关，许多人在十几岁和成年早期就死于肺部并发症。虽然肺部感染经常发生在患有A-T的人身上，但其他人在没有明显感染的情况下会经历肺功能下降。A-T患者肺功能下降的潜在原因包括慢性吸入、神经状况恶化、免疫缺陷、脊柱侧弯、手术和其他非呼吸系统相关疾病。 有趣的是，尽管患有A-T的人不会出现原发性肌肉无力，但他们的神经状态恶化往往会导致肌肉协调性受损，表现为浅呼吸、弱咳嗽和启动深呼吸的能力受损。在功能上，患有A-T的人可能与神经肌肉无力的人相似，都有呼吸储备受损，在睡眠期间发生呼吸衰竭以及患有呼吸系统疾病或压力的风险增加。因此，正如在神经肌肉无力的人身上发现的那样，夜间低氧血症也可能是A-T患者呼吸储备减少的早期标志。此外，由于ATM基因已知可以减轻缺氧/复氧过程中的氧化应激，A-T基因缺陷的人可能会因夜间低氧血症而导致氧化应激和炎症增加。在这项建议中，我们假设A-T患者的肺储备减少，表现为与已公布的对照组相比夜间低氧血症增加，与已公布的正常值相比，A-T患者夜间低氧血症患者血清中的炎症标志物增加。这些假设将通过以下具体目标加以解决： 具体目标1：确定接受夜间多导睡眠图检查的A-T患者与已公布的对照组相比，是否存在夜间低氧血症的增加。 具体目标2：通过夜间多导睡眠图确定A-T和夜间低氧血症患者是否也有C-反应蛋白、白细胞介素8和肿瘤坏死因子-1的升高。与公布的正常值相比。 如果青少年和患有房颤的年轻人在睡眠期间夜间低氧血症增加，那么可以采取诸如补充氧气和/或无创呼吸机等干预措施来改善这些人的氧合和异常呼吸。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nighttime Hypoxemia and Inflammation in Teenagers and Young Adults with Ataxia Telangiectasia ABSTRACT Ataxia Telangiectasia (A-T) is a genetic condition found in people with mutations in the ataxia telangiectasia gene (ATM). The ATM gene is activated in response to double-strand (ds) DNA breakage. People with A-T are particularly sensitive to the detrimental effects of oxidative stress. These stresses include among others, exposure to ionizing radiation (IR) and hypoxia/re-oxygenation injury. Cells defective in ATM may die or become senescent when exposed to oxidative stress, thus altering the injury response and impairing recovery. A-T is associated with frequent pulmonary exacerbations with many people succumbing to pulmonary complications during their teenage and early adult years. Although pulmonary infections occur often in individuals with A-T, others experience decline in lung function in the absence of overt infections. Potential causes of lung decline in people with A-T include chronic aspiration, worsening neurological status, immunodeficiency, scoliosis, surgery and other non-respiratory related illnesses. Interestingly, although people with A-T do not develop primary muscle weakness, their deterioration in neurological status can often lead to impaired muscle coordination manifested by shallow respirations, weak cough and an impaired ability to initiate a deep breath. Functionally people with A-T may be similar to people with neuromuscular weakness, with both having impaired respiratory reserve, and being at increased risk for developing respiratory failure during sleep and with respiratory illnesses or stress. Therefore as found in people with neuromuscular weakness, nighttime hypoxemia may also be an early marker of decreased respiratory reserve in people with A-T. Also since the ATM gene is known to attenuate oxidative stress during hypoxia/re-oxygenation, people with defects in the A-T gene may have an increase in oxidative stress and inflammation in response to nighttime hypoxemia. In this proposal we hypothesize that individuals with A-T have decreased pulmonary reserve, manifested by an increase in nighttime hypoxemia compared to published controls and that markers of inflammation are increased in the serum of A-T people with nighttime hypoxemia compared to published normal values. These hypotheses will be addressed through the following specific aims: Specific Aim #1: To determine if individuals with A-T, who undergo an overnight polysomnogram, have an increase in nighttime hypoxemia compared to published- controls. Specific Aim #2: To determine if individuals with A-T and nighttime hypoxemia by overnight polysomnogram, also have an increase in c-reactive protein, interleukin-8 and TNF-? compared to published normal values. If nighttime hypoxemia is increased in teenagers and young adults with A-T during sleep, then interventions such as supplemental oxygen and/or non-invasive ventilation could be instituted to improve oxygenation and abnormal breathing in these individuals.