Novel role for adiponectin-enhancing drugs for asthma in the obese

描述（由申请人提供）：哮喘是一种慢性肺部疾病，影响8.2%的美国成年人，尤其是肥胖者。目前对哮喘的治疗主要涉及吸入皮质类固醇，但这些药物对肥胖个体的效果较差。因此，发现针对肥胖个体的更有效的哮喘药物的需求尚未得到满足。最近的研究表明，在一些人群中，低浓度的脂联素（一种独特的脂肪组织抗炎产物）预示着哮喘的发生和更严重的哮喘临床严重程度。此外，低脂联素与抑郁症和缺血性心血管疾病相似。有效的脂联素增强药物包括抗糖尿病药物噻唑烷二酮类（TZD）和抗高血压药物血管紧张素受体阻滞剂类（ARB）。我们的首要假设是，在肥胖成人中使用脂联素增强药物可以帮助预防或治疗哮喘、抑郁症和缺血性心血管疾病。特异性目的1：确定脂联素增强药物对伴有糖尿病和/或高血压的肥胖受试者哮喘、抑郁或缺血性心血管疾病的影响。根据我们的初步数据，我们的主要假设是，与使用其他抗糖尿病和/或抗高血压药物相比，使用TZD和/或ARB与发生哮喘事件的风险较低相关，并且这种相关性在女性中强于男性。我们的次要假设是，在这一人群中，抑郁症和缺血性心血管疾病的发生率也有类似的有益影响。这项拟议的研究使用退伍军人管理局（VA）国家数据系统，对20多年来的美国退伍军人进行了纵向调查。我们将对每种疾病进行平行分析，我们首先在“基线”访问中排除流行疾病，并在随后的访问中分析偶发疾病。特定目标2：确定脂联素增强药物对患有该疾病（即哮喘、抑郁症或缺血性心血管疾病）、肥胖、合并糖尿病和/或高血压的受试者的疾病并发症风险的影响。根据我们的初步数据，我们的主要假设是，在我们的哮喘人群亚组中，使用TZD和/或ARB与使用其他抗糖尿病和/或抗高血压药物相比，哮喘恶化的风险较低，并且这种相关性在女性中强于男性。我们的次要假设是，在急诊室就诊或因抑郁症或缺血性心血管疾病住院方面，也可以看到类似的有益效果。对于Specific Aim 2，我们将在每个统计模型中只包括那些患有流行疾病的人，并分析与该疾病相关的并发症风险。生存分析将用于研究目标1和目标2中的事件。如果我们的研究表明，脂联素增强药物有利于影响低脂联素血症相关疾病的自然历史，这将有助于制定预防和治疗肥胖患者哮喘、抑郁症和缺血性心血管疾病的新策略。

DESCRIPTION (provided by applicant): Asthma is a chronic lung disease that affects 8.2% of all American adults, particularly obese individuals. Current treatment for asthma primarily involves inhaled corticosteroids but these drugs are less effective among obese individuals. There is therefore an unmet need to discover more efficacious asthma medications targeting obese individuals. Recent research has shown that low serum concentrations of adiponectin, a unique anti-inflammatory product of adipose tissue, predict both incident asthma and worse clinical severity of asthma in some populations. In addition, low adiponectin is similarly associated with depression and ischemic cardiovascular disease. Potent adiponectin-enhancing drugs include the antidiabetic drug class of thiazolidinediones (TZD) and antihypertensive drug class of angiotensin receptor blockers (ARB). Our overarching hypothesis is that use of adiponectin-enhancing drugs among obese adults can help prevent or treat asthma as well as depression and ischemic cardiovascular disease. Specific Aim 1: To determine the effect of adiponectin-enhancing drugs on incident asthma, depression or ischemic cardiovascular disease among obese subjects with concomitant diabetes and/or hypertension. Based upon our preliminary data, our working primary hypothesis is that TZD and/or ARB use is associated with a lower risk for developing incident asthma than use of other antidiabetic and/or antihypertensive drugs and this association is stronger among women than men. Our secondary hypotheses are that similar beneficial effects are seen with respect to incident depression and incident ischemic cardiovascular disease in this population. The proposed study examines a longitudinal cohort of veteran Americans over two decades, using the Veterans Administration (VA) National Data System. We will conduct parallel analyses for each disease in which we first exclude prevalent disease at 'baseline' visit and analyze incident disease at subsequent visits. Specific Aim 2: To determine the effect of adiponectin-enhancing drugs on risk for disease complications among subjects with that disease (i.e. asthma, depression or ischemic cardiovascular disease) plus obesity plus concomitant diabetes and/or hypertension. Based upon our preliminary data, our working primary hypothesis is that TZD and/or ARB use in our population subgroup with asthma is associated with a lower risk for asthma exacerbations than use of other antidiabetic and/or antihypertensive drugs and this association is stronger among women than men. Our secondary hypotheses are that similar beneficial effects are seen with respect to emergency room visits or hospitalizations from depression or ischemic cardiovascular disease. For Specific Aim 2, we will include only those with prevalent disease in each statistical model and analyze risk for complications related to that disease. Survival analysis will be used to study the events in Aims 1 and 2. If our research shows that adiponectin-enhancing drugs favorably affect the natural history of diseases related to hypoadiponectinemia, it will help develop novel strategies for preventing and treating asthma as well as depression and ischemic cardiovascular disease in the obese.