Large Stress Proteins in Biology and Medicine

生物学和医学中的大应激蛋白

• 批准号: 8633425
• 负责人: Xiang-Yang Shawn Wang
• 金额: $ 30.09万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633425
• 关键词: Animal Model; Antigen Presentation Pathway; Antigen Targeting; Antigen-Presenting Cells; Antigens; Award; Biological; Biology; Client; Clinical; Clinical Trials; Communicable Diseases; Complex; Coupling; Cross Presentation; DNA; Data; Degradation Pathway; Development; Disease; Endoplasmic Reticulum; Exhibits; Fever; Goals; Heat shock proteins; Heat-Shock Response; Host Defense; Host Defense Mechanism; Hyperthermia; Immune; Immune response; Immune system; Immunity; Immunologics; In Vitro; Infection; Inflammation; Knowledge; Lead; Light; Malignant Neoplasms; Mediating; Medicine; Modeling; Molecular; Molecular Chaperones; Natural Immunity; Organism; Outcome; Pattern; Pattern Recognition; Pattern recognition receptor; Peptides; Process; Production; Property; Proteins; Quality Control; Recombinants; Regimen; Regulation; Research; Role; Signal Transduction; Staging; Stress; Synthetic Vaccines; System; T-Cell Activation; T-Lymphocyte; Temperature; Testing; Therapeutic; Therapeutic Intervention; Time; Ubiquitin; Vaccines; Work; base; biological adaptation to stress; cancer immunotherapy; clinically relevant; design; gp100 Antigen; immunoregulation; improved; insight; melanoma; microbial; multicatalytic endopeptidase complex; novel; novel strategies; pathogen; protein complex; public health relevance; receptor; response; stress protein; thermal stress; tumor

DESCRIPTION (provided by applicant): Large stress/heat shock proteins (LSPs) that are complexed in vitro with clinically relevant tumor protein antigens by heat shock have demonstrated highly potent antitumor efficacy in animal models. However, the molecular basis of immunoregulatory features of LSPs remains largely undetermined. Our initial work led to an unexpected finding that enhanced cross-presentation of melanoma protein antigen (Ag) by exogenously delivered LSP involved the endoplasmic reticulum-associated degradation (ERAD) machinery, an intracellular protein quality control system. In addition, for the first time we have discovered that LSPs actively interact with pathogen-derived molecules or PAMPs, resulting in synergistic activation of intracellular NOD-like receptor (NLR)/inflammasome. These observations, which implicate the molecular chaperoning underlying the essential immunologic activities of LSPs, lead us to hypothesize that LSPs are capable of engaging and bridging both innate and adaptive compartments through their highly efficient chaperoning functions. The overall objective of this application is to investigate the highly novel aspects of LSPs in interacting with a self tumor protein Ag and PAMP molecules, as well as distinct immune consequences. Furthermore, LSP-primed cellular responses under physiologically relevant fever-like thermal stress conditions will be assessed. As a consequence of these studies, a novel approach to further enhance the therapeutic potency of the chaperone vaccine regimen by integrating both Ag target and PAMP molecules will be evaluated. The following specific aims will be pursued to achieve the project goal: 1) Determine the protein quality control mechanisms underlying LSP-enhanced cross-presentation of tumor protein Ag. 2) Determine the capability of LSP to interact with PAMPs and modify the resultant immune outcomes. 3) Determine the antitumor efficacy of a modified chaperone vaccine regimen incorporating a PAMP-derived 'danger' signal. Given the common chaperoning property shared by different classes of heat shock proteins, successful completion of these studies will provide important insights into the unique biological activities of these ancient molecules. The proposed studies will also shed new light on the role of mild thermal stress/hyperthermia in the host response, which could be exploited therapeutically for immune modulation. A detailed understanding of the LSP action in host defense mechanisms should provide more effective and safe strategies for targeting cancer and other diseases of clinical importance.

描述（由申请人提供）：通过热休克在体外与临床相关肿瘤蛋白抗原复合的大应激/热休克蛋白（LSP）已在动物模型中表现出高效的抗肿瘤功效。然而，LSP 免疫调节特征的分子基础在很大程度上仍未确定。我们最初的工作带来了一个意想不到的发现，即通过外源递送的 LSP 增强黑色素瘤蛋白抗原 (Ag) 的交叉呈递涉及内质网相关降解 (ERAD) 机制，这是一种细胞内蛋白质质量控​​制系统。此外，我们首次发现LSP与病原体衍生分子或PAMP积极相互作用，导致细胞内NOD样受体（NLR）/炎症小体的协同激活。这些观察结果暗示了 LSP 基本免疫活性背后的分子伴侣作用，使我们推测 LSP 能够通过其高效的伴侣功能参与和桥接先天性和适应性区室。该应用的总体目标是研究 LSP 在与自身肿瘤蛋白 Ag 和 PAMP 分子相互作用方面的高度新颖的方面，以及独特的免疫后果。此外，还将评估生理相关的发烧样热应激条件下 LSP 引发的细胞反应。这些研究的结果是，将评估一种通过整合 Ag 靶标和 PAMP 分子来进一步增强伴侣疫苗方案治疗效力的新方法。为了实现该项目目标，将追求以下具体目标：1）确定LSP增强肿瘤蛋白Ag交叉呈递的蛋白质质量控​​制机制。 2) 确定 LSP 与 PAMP 相互作用并改变由此产生的免疫结果的能力。 3) 确定结合 PAMP 衍生“危险”信号的改良伴侣疫苗方案的抗肿瘤功效。鉴于不同类别的热休克蛋白具有共同的陪伴特性，这些研究的成功完成将为了解这些古老分子的独特生物活性提供重要的见解。拟议的研究还将揭示轻度热应激/高温在宿主反应中的作用，这可以在治疗上用于免疫调节。详细了解 LSP 在宿主防御机制中的作用应该为针对癌症和其他具有临床重要性的疾病提供更有效和安全的策略。