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，埃默里酒精和肺部生物学中心的主要目标一直是 开发新的有效的治疗方法，可以减轻甚至逆转病理生理 酒精对肺部的影响。前两个资金周期致力于阐明 诱发“酒精肺表型”的基本机制。我们的实验发现 阐明氧化应激(包括严重的谷胱甘肽耗竭)、锌的核心作用 PPARγ的表达和功能减弱，从而影响酒精的作用。 最近，我们发现酒精抑制转录因子Nrf2的活动 激活抗氧化剂反应元件(ARE)并以编程方式诱导表达 需要数百个基因(包括那些涉及谷胱甘肽稳态的基因)来防御 对抗炎症压力。此外，NRF2和PPARγ活性似乎依赖于锌和 因此，这些途径可能是相互依赖的，因此是酒精协同作用的靶点。 值得注意的是，在慢性艾滋病毒感染期间，这些相同的途径被作为靶点，我们已经确定 酒精和HIV相关蛋白对肺上皮细胞和巨噬细胞的相加毒性 功能。因为我们的中心研究人员也在进行转化性临床试验 我们有独特的能力来研究酒精和酒精的联合作用 以及这种组合如何可能对开发有效的治疗方法构成挑战。这些 这些发现不仅揭示了酒精使肺易感的机制 但也已经确定了中心调查人员正在测试的候选治疗目标 在实验模型和临床试验中。这个新的项目3将协调和指导我们的 “临床试验流水线”和牧羊人的发现从实验室到干预试验。 项目3的目标是：1)确定膳食补充锌的效果 和/或在逆转酒精使用障碍受试者的酒精肺表型方面也是如此， 同时，经常饮酒如何影响膳食锌+SAME逆转肺功能的效果 艾滋病毒携带者的功能障碍。2)开发我们的实验和临床翻译 酒精诱导抑制PPARγ信号转导的临床研究 如果用PPARγ配体吡格列酮治疗可以逆转酒精性肺表型 酒精使用障碍的受试者。3)与项目1和2合作，确定NRF2 激活剂单独或与锌联合使用可以迅速逆转酒精中毒的肺表型。 体内和体外人肺泡巨噬细胞的动物模型，并将这些研究转化为 萝卜硫素等药物单独或与锌联合治疗慢性阻塞性肺疾病的临床试验 酒精使用障碍。在我们即将进行的这些试验中，任何一项的成功都将产生巨大的 对与酒精使用障碍作斗争的个人的影响，包括那些也活着的人 艾滋病毒携带者。