ALCOHOL, NUTRITION, AND IMMUNOMODULATION

酒精、营养和免疫调节

基本信息

  • 批准号:
    2882035
  • 负责人:
  • 金额:
    $ 29.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1996
  • 资助国家:
    美国
  • 起止时间:
    1996-03-01 至 2001-02-28
  • 项目状态:
    已结题

项目摘要

Tumor necrosis factor (TNF) is a macrophage/monocyte-derived inflammatory cytokine whose dysregulation has been shown by us and others to play an important role in the pathophysiology of several forms of liver injury including that observed in alcoholic liver disease (ALD). TNF also has been postulated to play a pivotal role in the metabolic complications and wasting of Acquired Immunodeficiency Syndrome (AIDS). There are great similarities between the metabolic abnormalities/complications of AIDS and ALD including anorexia, cachexia, immune suppression, hypoalbuminemia, increased acute phase reactants and edema, to name only a few. We have demonstrated increased plasma TNF, increased monocyte TNF production, and increased hepatic immunohistochemical staining for TNF in patients with ALD. Mitochondrial dysfunction/structural damage is an early event in ALD, and it has also been postulated to play a role in organ dysfunction in AIDS. TNF, per se, causes mitochondrial dysfunction/damage including inhibition of respiration, superoxide generation, and ultimately cell injury. Impairment of normal mitochondrial respiration markedly enhances TNF cytotoxicity. TNF mediated cytotoxicity is thought to be an oxidant injury, and TNF induction of the mitochondrial antioxidant manganous superoxide dismutase (MnSOD) is an endogenous protective mechanism to prevent ongoing TNF cytotoxicity. Regulation of cytokines such as TNF has become a focal point for therapeutic intervention in many diseases including ALD and AIDS. NFkappaB is a transcription factor for several cytokines including TNF and for the HIV virus. NFkappaB is activated by reactive oxygen intermediates, and this activation can be blocked by antioxidants such as vitamin E (Vit E) and glutathione (GSH)-enhancing agents in certain transformed cell lines. It is our working hypothesis that TNF plays an etiologic role in many of the clinical/biochemical abnormalities observed in ALD and AIDS. We postulate that chronic alcohol abuse and HIV infection cause increased gut permeability and endotoxemia, depletion of many nutrient antioxidants (e.g., GSH, Vit E), generation of reactive oxygen intermediates, activation of NFkappaB, increased TNF production, mitochondrial dysfunction with mitochondrial GSH depletion, and ultimately wasting and organ dysfunction including liver injury. The overall research goals of this laboratory are to further define mechanisms and modulatory pathways whereby cytokines, such as TNF, induce metabolic disturbances/liver injury in ALD and in AIDS, with the ultimate goal being development of specific "anticytokine" therapy for ALD and for AIDS. The specific objectives in this proposal (initially performed in ALD patients) are to: 1) Evaluate dysregulated cytokine (TNF, IL-8) production in ALD, the role of antioxidant status and NFkappaB activation in modulating this cytokine production and the role of "anticytokine" therapy; 2) Determine the role of mitochondrial dysfunction/protection in alcohol/TNF-mediated hepatotoxicity; and 3) Determine whether unique forms of antioxidant therapy attenuate dysregulated TNF production and mitochondrial dysfunction in patients with ALD. This research spans the spectrum from molecular cellular studies to applied human investigations, with the ultimate goal being improved knowledge and therapy for these two devastating disease processes with overlapping metabolic complications.
肿瘤坏死因子(TNF)是一种巨噬细胞/单核细胞衍生的炎症因子, 我们和其他人已经证明,这种细胞因子的失调, 在几种形式的肝损伤的病理生理学中的重要作用 包括在酒精性肝病(ALD)中观察到的。 TNF也有 被认为在代谢并发症中起着关键作用, 获得性免疫缺陷综合征(艾滋病)。 存在很大 艾滋病的代谢异常/并发症与 ALD包括厌食、恶病质、免疫抑制、低白蛋白血症, 增加急性期反应物和水肿,仅举几例。 我们有 显示血浆TNF增加,单核细胞TNF产生增加, 肝肿瘤患者的TNF免疫组化染色增加 ALD。 线粒体功能障碍/结构损伤是一个早期事件, ALD,它也被假定在器官功能障碍中发挥作用 艾滋病 TNF本身引起线粒体功能障碍/损伤,包括 抑制呼吸、超氧化物生成,并最终抑制细胞 损伤 正常线粒体呼吸的损伤显著增强了 TNF细胞毒性。 TNF介导的细胞毒性被认为是一种氧化剂 损伤和TNF诱导的线粒体抗氧化剂锰 超氧化物歧化酶(MnSOD)是一种内源性保护机制, 防止持续的TNF细胞毒性。 细胞因子如TNF的调节 成为许多疾病治疗干预的焦点 包括ALD和艾滋病。 NF κ B是一种转录因子, 细胞因子包括TNF和HIV病毒。 NF κ B被激活, 活性氧中间体,这种激活可以被阻断, 抗氧化剂,如维生素E(Vit E)和谷胱甘肽(GSH)-增强 某些转化细胞系中的药物。 我们的假设是 TNF在许多临床/生化疾病中起着病因学作用, 在ALD和艾滋病中观察到的异常。 我们假设长期酗酒 滥用和HIV感染导致肠道通透性增加和内毒素血症, 许多营养抗氧化剂的耗尽(例如,GSH、维生素E),产生 活性氧中间体,NF κ B活化,TNF增加 产生,线粒体功能障碍伴线粒体GSH耗竭, 并最终导致消耗和器官功能障碍,包括肝损伤。 的 该实验室的总体研究目标是进一步确定机制 以及细胞因子如TNF诱导代谢的调节途径 ALD和AIDS中的干扰/肝损伤,最终目标是 开发针对ALD和AIDS的特异性“抗细胞因子”疗法。 的 本提案的具体目标(最初在ALD患者中进行) 1)评估ALD中失调的细胞因子(TNF,IL-8)产生, 抗氧化状态和NFkappaB激活在调节中的作用 细胞因子的产生和“抗细胞因子”治疗的作用; 2)确定 线粒体功能障碍/保护在酒精/TNF介导 肝毒性;和3)确定是否独特形式的抗氧化剂 治疗减弱失调的TNF产生和线粒体 ALD患者的功能障碍。 这项研究涵盖了从 从分子细胞研究到应用人类研究, 最终目标是改善这两个人的知识和治疗 破坏性的疾病过程与重叠的代谢并发症。

项目成果

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CRAIG J. MCCLAIN其他文献

CRAIG J. MCCLAIN的其他文献

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{{ truncateString('CRAIG J. MCCLAIN', 18)}}的其他基金

Inflammation Resolving Lipid Mediators: Novel Therapy for Alcohol AssociatedLiver Disease
消炎脂质介质:酒精相关性肝病的新疗法
  • 批准号:
    10590047
  • 财政年份:
    2023
  • 资助金额:
    $ 29.44万
  • 项目类别:
Administrative Supplement to Hepatobiology and Toxicology COBRE
肝生物学和毒理学 COBRE 行政增刊
  • 批准号:
    10399887
  • 财政年份:
    2021
  • 资助金额:
    $ 29.44万
  • 项目类别:
Alcoholic Hepatitis Network 3/9 University of Louisville
酒精性肝炎网络 3/9 路易斯维尔大学
  • 批准号:
    9752421
  • 财政年份:
    2018
  • 资助金额:
    $ 29.44万
  • 项目类别:
Alcoholic Hepatitis Network 3/9 University of Louisville
酒精性肝炎网络 3/9 路易斯维尔大学
  • 批准号:
    10434741
  • 财政年份:
    2018
  • 资助金额:
    $ 29.44万
  • 项目类别:
Alcoholic Hepatitis Network 3/9 University of Louisville
酒精性肝炎网络 3/9 路易斯维尔大学
  • 批准号:
    10202391
  • 财政年份:
    2018
  • 资助金额:
    $ 29.44万
  • 项目类别:
Pilot Trial UO1 DUR-928
试点试验 UO1 DUR-928
  • 批准号:
    10441277
  • 财政年份:
    2018
  • 资助金额:
    $ 29.44万
  • 项目类别:
Pilot Trial UO1 DUR-928
试点试验 UO1 DUR-928
  • 批准号:
    10201423
  • 财政年份:
    2018
  • 资助金额:
    $ 29.44万
  • 项目类别:
Pilot Trial UO1 DUR-928
试点试验 UO1 DUR-928
  • 批准号:
    9792232
  • 财政年份:
    2018
  • 资助金额:
    $ 29.44万
  • 项目类别:
Hepatobiology and Toxicology COBRE
肝脏生物学和毒理学 COBRE
  • 批准号:
    10377890
  • 财政年份:
    2016
  • 资助金额:
    $ 29.44万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10026251
  • 财政年份:
    2016
  • 资助金额:
    $ 29.44万
  • 项目类别:

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