Enhancing Immunotherapy through Toll Like Receptors

通过 Toll 样受体增强免疫治疗

• 批准号: 7288368
• 负责人: CYNTHIA A LEIFER
• 金额: $ 17.35万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7288368
• 关键词: Adjuvant; Adjuvanticity; Amino Acids; Antigen-Presenting Cells; Bacterial DNA; Binding; Biochemical; Biological Assay; Biology; Cancer Vaccines; Cell surface; Cells; Class; Confocal Microscopy; Cytoplasmic Tail; DNA; Data; Development; Double-Stranded RNA; Endoplasmic Reticulum; Family; Goals; Grant; Human; Immune response; Immune system; Immunotherapy; Knowledge; Ligand Binding; Ligands; Light; Localized; Malignant Neoplasms; Modification; Molecular; Molecular Biology; Molecular Profiling; Mutagenesis; Mutation; Nucleic Acids; Pathway interactions; Pattern; Pattern Recognition; Pattern recognition receptor; Peptides; Pharmaceutical Preparations; Physiologic pulse; Play; Property; Pulse taking; Receptor Signaling; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Surface; T-Lymphocyte; TLR3 gene; TLR7 gene; TLR8 gene; TLR9 gene; Testing; Toll-like receptors; Tumor Antigens; Vaccination; Vaccine Adjuvant; base; cancer immunotherapy; career; cellular targeting; cytokine; glycosylation; human TLR3 protein; human TLR7 protein; immunogenicity; improved; interest; loss of function; microorganism; mouse model; novel; novel strategies; novel therapeutics; pathogen; programs; receptor; research study; response; trafficking; tumor

DESCRIPTION (provided by applicant): The goal of cancer immunotherapy is to elicit anti-tumor immune responses. Injecting tumor antigens for immunotherapy results in T cell responses that are weak and ineffective due to a lack of good adjuvants. Recent emphasis has been on pathogen associated molecular patterns (PAMPs) as candidate vaccine adjuvants. PAMPs are molecular signatures that define classes of microorganisms and induce potent immune responses. The long-term goal of the proposed studies is to understand the molecular mechanisms of activation of PAMPs on their receptors, Toll like receptors (TLRs). Modulation of TLRs and modification of PAMPs will greatly enhance cancer vaccine adjuvanticity thereby improving immunotherapy of cancer. In this grant period we will determine control mechanisms for PAMP recognition and receptor trafficking in a subfamily of Toll like receptors (3, 7, 8 and 9). These transmembrane Toll like receptors share the properties that they are not expressed at the cell surface and that they recognize nucleic acids such as dsRNA (TLR3), ssRNA (TLR7 and TLR8) and CpG containing DNA (TLR9). We hypothesize that nucleic acid recognizing Toll like receptors share localization, trafficking and PAMP recognition mechanisms that are controlled by discrete sequences in the cytoplasmic and ectodomains. We will test the hypothesis in two specific aims. First, we will determine the molecular mechanisms of localization and trafficking of nucleic acid recognizing Toll like receptors in response to PAMPs. Second, we will determine the specific binding regions on TLRs for the corresponding PAMP ligand. This information will fill gaps in the knowledge of Toll like receptor-PAMP biology: the molecular basis of ligand recognition, and the role of cellular targeting in controlling signaling. This information will allow the development of novel therapeutic strategies to modulate the immune responses to improve cancer vaccine adjuvants. This career transition grant will allow me to develop a research program focused on new ways to exploit TLR-PAMP biology for the treatment of human cancer.

描述（由申请人提供）：癌症免疫治疗的目标是引发抗肿瘤免疫应答。由于缺乏良好的佐剂，注射肿瘤抗原用于免疫治疗导致T细胞应答弱且无效。最近的重点是病原体相关分子模式（PAMP）作为候选疫苗佐剂。PAMP是定义微生物类别并诱导有效免疫应答的分子标记。这些研究的长期目标是了解PAMP激活其受体Toll样受体（TLR）的分子机制。TLR的调节和PAMP的修饰将大大增强癌症疫苗的佐剂性，从而改善癌症的免疫治疗。在本研究期间，我们将确定Toll样受体亚家族中PAMP识别和受体运输的控制机制（3，7，8和9）。这些跨膜Toll样受体共有的特性是它们不在细胞表面表达，并且它们识别核酸如dsRNA（TLR 3）、ssRNA（TLR 7和TLR 8）和含CpG的DNA（TLR 9）。我们假设识别Toll样受体的核酸共享由细胞质和胞外域中的离散序列控制的定位、运输和PAMP识别机制。我们将在两个具体目标中检验这一假设。首先，我们将确定定位和运输的核酸识别Toll样受体的分子机制，以PAMPs。其次，我们将确定TLR上相应PAMP配体的特异性结合区域。这些信息将填补Toll样受体-PAMP生物学知识的空白：配体识别的分子基础，以及细胞靶向在控制信号传导中的作用。这些信息将允许开发新的治疗策略来调节免疫应答以改善癌症疫苗佐剂。这项职业过渡补助金将使我能够开发一个研究项目，重点是利用TLR-PAMP生物学治疗人类癌症的新方法。

项目成果

Genetic diversity of Toxoplasma gondii isolates from chickens from Brazil.

• DOI: 10.1016/j.vetpar.2008.07.036
• 发表时间: 2008-11-07
• 期刊: VETERINARY PARASITOLOGY
• 影响因子: 2.6
• 作者: Dubey, J. P.;Velmurugan, G. V.;Chockalingam, A.;Pena, H. F. J.;de Oliveira, L. Nunes;Leifer, C. A.;Gennari, S. M.;Oliveira, L. M. G. Bahia;Su, C.
• 通讯作者: Su, C.