Mechanisms of Vanilloid Receptor-Induced Cell Death

描述（由申请人提供）：急性和慢性吸入有毒物质，如空气中的颗粒物质和各种有机异种生物，会损害呼吸组织。我们最近发现辣椒素，以雾化的自卫武器的形式，引起炎症和呼吸道上皮细胞损伤。辣椒素引起上皮细胞损伤的确切机制尚未确定。这项应用的假设是：人肺细支气管上皮细胞中香草受体（VR1、vr5’sv、VRL-1和VRL-2）的表达和活性决定了细胞对辣椒素和其他呼吸道毒物的细胞毒性的易感性。本研究的长期目标是为VR1和其他香草样受体在各种呼吸道毒物（包括辣椒素和空气中的颗粒物）介导气道上皮细胞损伤中的作用提供重要的见解。这项新应用的具体目标是：1)建立各种香草受体配体和其他香草受体激动剂的细胞死亡（即细胞凋亡或坏死）的效力和机制；2)确定VR1表达水平改变对细胞毒性易感性的影响；3)评估VR1特定氨基酸残基和n端序列对VR1介导细胞毒性能力的结构功能关系；4)确定vr5 'sv、VRL-2和/或新发现的香草样受体样蛋白在肺细胞对呼吸道毒物易感性中的作用。这些目标将提供：1)关于暴露于有毒物质的呼吸上皮细胞中细胞毒性反应的关键介质的重要见解；2)特定呼吸道刺激物/毒素毒性的详细机制，并能够将这些机制外推到其他呼吸道毒物；3)可操纵的特定生化靶点，以改善各种呼吸系统疾病；4)深入了解影响细胞对气道毒物易感性的内源性调节机制。这些研究结果可用于预测人体对自卫武器中呼吸道刺激物的反应，并确定香草样受体肺上皮细胞的功能。

DESCRIPTION (provided by applicant): Acute and chronic inhalation of toxicants, such as airborne particulate material and various organic xenobiotics, can damage respiratory tissues. We have recently discovered that capsaicin, in the form of aerosolized self-defense weaponry, caused inflammation and respiratory epithelial cell damage. The precise mechanism(s), by which capsaicin caused epithelial cell damage, has not been established. The hypothesis of this application is: the expression and activity of vanilIoid receptors (VR1, VR.5 'sv, VRL-1, and VRL-2) by human lung bronchiolar epithelial cells dictates cellular susceptibility to cytotoxicity by capsaicin and other respiratory toxicants. The long-term goal of this research is to provide vital insight into the role of VR1 and other vanilloid receptors in mediating airway epithelial cell damage by various respiratory toxicants, including capsaicin and airborne particulates. The specific goals of this new application are: 1) to establish the potency and mechanism(s) of cell death (i.e., apoptosis or necrosis) for a variety of vanilloid receptor ligands and other vanilloid receptor agonists; 2) to determine the effects of altered levels of VR1 expression on cellular susceptibility to cytotoxicity; 3) to assess the structure function relationships for specific VR1 amino acid residues and N-terminal sequences on the ability of VR1 to mediate cytotoxicity; and 4) To determine the contribution of VR.5'sv, VRL-2, and/or newly discovered Vanilloid Receptor-Like proteins to lung cell susceptibility to respiratory toxicants. These aims will provide: 1) vital insight concerning key mediators of cytotoxic responses in respiratory epithelial cells exposed to toxicants; 2) detailed mechanisms of toxicity of specific respiratory irritants/toxins with the ability to extrapolate these mechanisms to other respiratory toxicants; 3) specific biochemical targets that can be manipulated to ameliorate a variety of respiratory disorders and diseases; and 4) insight into endogenous regulatory mechanisms that influence cellular susceptibility to airway toxicants. Outcomes of these investigations can be utilized to predict human responses to respiratory irritants in self-defense weaponry and define the functions of vanilloid receptors lung epithelial cells.