Developing and testing novel therapies for the alcoholic lung: our clinical trials pipeline

开发和测试酒精肺的新疗法：我们的临床试验管道

• 批准号: 9757650
• 负责人: David Marshall Guidot
• 金额: $ 30.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-25 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757650
• 关键词: Abstinence; Acute Lung Injury; Affect; Alcohol abuse; Alcohol consumption; Alcohols; Alveolar; Alveolar Macrophages; Animal Model; Antioxidants; Biological; Biology; Chronic; Clinical; Clinical Research; Clinical Trials; Collaborations; Dietary Supplementation; Dietary Zinc; Discipline; Environment; Epidemic; Epithelial; Equilibrium; Experimental Animal Model; Experimental Models; Face; Faculty; Functional disorder; Funding; Genes; Glutathione; Goals; HIV; HIV Infections; Health; Healthcare; Homeostasis; Human; Impairment; Individual; Inflammatory; Infrastructure; Injury; Intervention; Intervention Trial; Laboratories; Life; Ligands; Lung; Lung diseases; Mediating; Molecular; Mothers; Oxidation-Reduction; Oxidative Stress; PPAR gamma; Pathway interactions; Phenotype; Pioglitazone; Pneumonia; Postdoctoral Fellow; Pregnancy; Premature Infant; Proteins; Recording of previous events; Research Personnel; Respiratory physiology; Response Elements; Risk; Role; S-Adenosylmethionine; School Teachers; Scientist; Series; Signal Transduction; Societies; Stress; Sulforaphane; Testing; Toxic effect; Training; Training Programs; Translating; Zinc; Zinc deficiency; Zinc supplementation; activating transcription factor; addiction; alcohol and other drug; alcohol effect; alcohol misuse; alcohol research; alcohol use disorder; chronic alcohol ingestion; effective therapy; epidemiology study; experimental study; healthy lifestyle; high risk; in vivo Model; macrophage; member; multidisciplinary; nature center; novel; novel therapeutics; pre-doctoral; prevent; problem drinker; success; targeted treatment; therapeutic target; therapy development; transcription factor; translational clinical trial; translational study; treatment program

Since its inception, the primary goal of the Emory Alcohol and Lung Biology Center has been to develop novel and effective treatments that can mitigate or even reverse the pathophysiological effects of alcohol on the lung. The first two funding cycles were dedicated to elucidating the fundamental mechanisms that induce the ‘alcoholic lung phenotype’. Our experimental findings have elucidated central roles for oxidative stress (including profound glutathione depletion), zinc deficiency, and decreased expression and function of PPARγ in mediating the effects of alcohol. More recently we identified that alcohol inhibits the actions of Nrf2, the transcription factor that activates the anti-oxidant response element (ARE) and programmatically induces the expression of hundreds of genes (including those involved in glutathione homeostasis) required to defend against inflammatory stresses. Moreover, Nrf2 and PPARγ activity appear to be zinc-dependent and therefore these pathways may be interdependent and therefore coordinately targeted by alcohol. Remarkably, these same pathways are targeted during chronic HIV infection, and we have determined that alcohol and HIV- related proteins have additive toxicities on lung epithelial and macrophage function. As our Center investigators are also engaged in translational clinical trials in HIV-mediated lung disease, we have the unique capacity to study the combined effects of alcohol and HIV and how this combination may pose a challenge to developing effective therapies. These discoveries have not only revealed the mechanisms by which alcohol renders the lung susceptible to injury but have also identified candidate therapies targets that Center investigators are testing in experimental models and clinical trials. This new Project 3 will coordinate and direct our ‘clinical trials pipeline’ and shepherd discoveries from the laboratory to interventional trials. The goals of Project 3 are to: 1) Determine the efficacy of dietary supplementation with zinc and/or SAMe in reversing the alcoholic lung phenotype in subjects with alcohol use disorders and, in parallel, how regular alcohol use affects the efficacy of dietary zinc + SAMe in reversing lung dysfunction in individuals living with HIV. 2) Exploit our experimental and clinical translational studies on alcohol-induced inhibition of PPARγ signaling to conduct a clinical trial to determine if treatment with the PPARγ ligand pioglitazone can reverse the alcoholic lung phenotype in subjects with alcohol use disorders. 3) In collaboration with Projects 1 and 2, determine if Nrf2 activators, alone or in combination with zinc, can rapidly reverse the alcoholic lung phenotype in animal models in vivo and in human alveolar macrophages ex vivo, and translate these studies to a clinical trial of agents such as sulforaphane, alone or in combination with zinc, in subjects with alcohol use disorders. Success in any of these trials in our pipeline will have enormous implications for individuals struggling with alcohol use disorders, including those also living with HIV.

自成立以来，Emory酒精和肺生物学中心的主要目标是 开发可减轻甚至逆转病理生理的新颖有效的治疗方法 酒精对肺的影响。前两个资金周期致力于阐明 诱导“酒精肺表型”的基本机制。我们的实验发现有 阐明氧化应激的中心作用（包括深谷胱甘肽耗竭），锌 缺乏症，改善了PPARγ在介导酒精作用中的表达和功能。 最近，我们发现酒精抑制了转录因子NRF2的作用 激活抗氧化响应元件（IS），并以编程方式诱导表达 需要捍卫的数百个基因（包括参与谷胱甘肽稳态的基因） 反对炎症应力。此外，NRF2和PPARγ活性外观依赖于锌，并且 因此，这些途径可能是相互依存的，因此可以由酒精进行协调。 值得注意的是，这些相同的途径是在慢性艾滋病毒感染期间针对的，我们已经确定 酒精和与HIV相关的蛋白质增加了对肺上皮和巨噬细胞的毒性 功能。由于我们的中心调查人员还参与了翻译的临床试验 艾滋病毒介导的肺部疾病，我们具有研究酒精和综合作用的独特能力 艾滋病毒以及这种组合如何对开发有效疗法构成挑战。这些 发现不仅揭示了酒精使肺部容易受到影响的机制 受伤，但还确定了中心研究人员正在测试的候选疗法目标 在实验模型和临床试验中。这个新项目3将协调并指导我们 从实验室到介入试验的“临床试验管道”和牧羊人发现。 项目3的目标是：1）确定补充锌的饮食效率 和/或在逆转酒精使用障碍受试者中酒精性肺表型和/或相同 同时，常规饮酒如何影响饮食锌 +在反向肺中相同的效率 患有艾滋病毒的人的功能障碍。 2）利用我们的实验和临床翻译 关于酒精诱导的PPARγ信号传导抑制以进行临床试验的研究以确定 如果用PPARγ配体吡格列酮治疗可以逆转酒精肺表型 饮酒障碍的受试者。 3）与项目1和2合作，确定NRF2是否是否 单独或与锌结合的激活剂可以迅速逆转酒精肺表型 体内和人类肺泡巨噬细胞中的动物模型，并将这些研究转化为 单独或与锌联合使用的药物的临床试验， 酒精使用障碍。在我们的管道中的任何这些试验中的成功都将具有巨大的 对患有酒精使用障碍的个人的影响，包括那些也活着的人 与艾滋病毒。