STRUCTURE FUNCTION OF MOLECULES IN INNATE IMMUNITY

先天免疫中分子的结构功能

• 批准号: 6362347
• 负责人: Alan B Ezekowitz
• 金额: $ 35.78万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6362347
• 关键词: Escherichia coli; Orthomyxoviridae; Streptococcus agalactiae; antibody; collagen; communicable diseases; complement; disease /disorder model; gene mutation; genetically modified animals; immunoregulation; laboratory mouse; lectin; mannose; microorganism immunology; model design /development; protein binding; protein structure function

Innate immunity plays a key role in the host's early surveillance against an infectious challenge. The immediate barriers to noxious stimuli take on many guises. The molecules that are involved in innate immunity in higher organisms, like mice and men, often have their origins in very primitive life-forms that lack specific immunity. In this proposal, we aim to extend our investigations into one such molecule in which we have had a long-standing interest. The mannose-binding protein (a.k.a. the mannan-binding protein and mannose-binding lectin) may be considered as an ante-antibody . The role for the mannose-binding protein as an antecedent of antibodies is based on convincing in vitro evidence against an infectious agent during the lag period prior to the generation of a specific immune response. The goals of this proposal are to determine the precise in vivo role for the mannose-binding protein in host defense. We have generated MBP-A null mice that will allow a determination of whether an absolute or relative lack of the mannose-binding protein predisposes to infection. We plan to generate double knockout mice which will allow us to determine the relative roles of the mannose-binding protein, complement and natural antibodies in first line host defense. We also plan to define the structural basis by which the mannose-binding protein multimers bind ligands. It is anticipated that these structural studies will provide important new information as to how the mannose-binding protein is able to recognize the patterns of carbohydrates that adorn the surfaces of a wide range of bacterial, fungal and viral agents, yet interact with a paucity of self glycoproteins. The studies described in this proposal, if successful, will complement and add significant credence to the clinical observations that lack of the mannose-binding protein particularly in children below the age of two predisposes them to recurrent infections. The availability of recombinant mannose-binding protein will provide immediate opportunities for replacement therapy in selected individuals in a manner analogous to the use of gammaglobulin replacement in hypogammaglobulinemia.

先天免疫在主持人对感染性挑战的早期监视中起着关键作用。 有害刺激的直接障碍采取了许多伪造。 像小鼠和男性这样的较高生物体中涉及先天免疫的分子通常起源于缺乏特定免疫力的非常原始的生命形式。 在此提案中，我们旨在将调查扩展到我们一直具有兴趣的一个这样的分子中。 甘露糖结合蛋白（又称Mannan结合蛋白和甘露糖结合凝集素）可被视为抗体。 甘露糖结合蛋白作为抗体的先决性的作用是基于在产生特定免疫反应之前的滞后期间具有令人信服的体外证据。 该提案的目标是确定甘露糖结合蛋白在宿主防御中的确切体内作用。 我们已经产生了MBP-A NULL小鼠，该小鼠将确定绝对或相对缺乏甘露糖结合蛋白感染感染。 我们计划产生双基因敲除小鼠，这将使我们能够确定第一线宿主防御中甘露糖结合蛋白，补体和天然抗体的相对作用。 我们还计划定义甘露糖结合蛋白多聚体结合配体的结构基础。 可以预料，这些结构研究将提供有关甘露糖结合蛋白如何识别碳水化合物的模式的重要新信息，这些碳水化合物的模式装饰了各种细菌，真菌和病毒剂的表面，却与自我糖蛋白的缺乏相互作用。 该提案中描述的研究（如果成功）将补充并为缺乏甘露糖结合蛋白的临床观察结果增加并增加了可靠性，尤其是在两个低于两个年龄的儿童中，使他们倾向于复发感染。 重组甘露糖结合蛋白的可用性将为选定个体的替代疗法提供立即的机会，其方式类似于在低血糖蛋白血症中使用γ-球蛋白替代蛋白。