Enhancing Immunotherapy through Toll Like Receptors

通过 Toll 样受体增强免疫治疗

基本信息

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
项目类别：
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

项目摘要

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）：癌症免疫疗法的目的是引起抗肿瘤免疫反应。注射免疫疗法的肿瘤抗原导致T细胞反应由于缺乏良好的佐剂而弱且无效。最近的重点是病原体相关的分子模式（PAMP）作为候选疫苗佐剂。 PAMP是分子特征，定义微生物类别并诱导有效的免疫反应。拟议的研究的长期目标是了解PAMP在其受体上激活的分子机制，例如受体（TLR）。 TLR的调节和PAMP的修饰将大大增强癌症疫苗辅助性，从而改善癌症的免疫疗法。在此赠款期间，我们将确定在像受体类似受体的亚科（3、7、8和9）的亚科中识别症状和受体运输的控制机制。这些跨膜损失像受体一样，具有在细胞表面表达的特性，并且它们识别核酸，例如dsRNA（TLR3），ssRNA（TLR7和TLR8）和含有DNA的CpG（TLR9）。我们假设核酸识别像受体一样的TOLL具有定位，运输和PAMP识别机制，这些机制由细胞质和胞菌中的离散序列控制。我们将以两个具体目标来检验该假设。首先，我们将确定核酸的定位和运输的分子机制，以响应PAMP，识别受体像受体一样。其次，我们将确定相应的弹药配体TLR上的特定结合区域。这些信息将填补对受体板生物学等通行费的知识的空白：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，以调节免疫反应以改善癌症疫苗辅助因素。这项职业过渡赠款将使我能够制定一项研究计划，该研究计划针对新方法来利用TLR-PAMP生物学治疗人类癌症。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.