This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Nighttime Hypoxemia and Inflammation in Teenagers and Young Adults with Ataxia TelangiectasiaABSTRACTAtaxia 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.
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