Lupus Serum Signaling Through Toll-Like Receptor 9

通过 Toll 样受体 9 进行狼疮血清信号传导

• 批准号: 7417569
• 负责人: TERRY K MEANS
• 金额: $ 12.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7417569
• 关键词: Adaptor Signaling Protein; Anti-DNA Antibodies; Antigen-Antibody Complex; Autoimmunity; B Cell Proliferation; B-Lymphocytes; Binding; Blood; CCL2 gene; Cells; Cellular biology; Complex; CpG dinucleotide; Cytokine Gene; DNA; Dendritic Cells; Deposition; Development; Disease; Environment; Enzyme-Linked Immunosorbent Assay; Fostering; Frequencies; Gene Expression Profile; General Hospitals; Goals; IL8 gene; Immunoglobulin G; Inflammatory Response; Injection of therapeutic agent; Injury; Interferon-alpha; Interleukin-1 alpha; Investigation; Kinetics; Laboratories; Lupus; Lysosomes; Massachusetts; Measures; Mediating; Mentored Research Scientist Development Award; Mus; Natural Immunity; Oligonucleotides; Organ; Patients; Pattern recognition receptor; Play; Point Mutation; Polymerase Chain Reaction; Process; Production; Protein Microchips; Radiolabeled; Serum; Signal Transduction; Signal Transduction Pathway; Site; Surface Immunoglobulins; Symptoms; Systemic Lupus Erythematosus; TLR9 gene; Therapeutic; Thinking; Tissues; Transgenic Mice; Work; anti-dsDNA antibodies; cell type; chemokine; cytokine; experience; macrophage; pathogen; radiotracer; receptor; response; skills; trafficking; transcription factor

DESCRIPTION (provided by applicant): With the proposed Mentored Research Scientist Development Award (K01), the applicant will build upon his prior experiences in studying innate immunity to enhance his skills in cell biology, signal transduction and autoimmunity. The laboratory of Dr. Andrew D. Luster at the Massachusetts General Hospital will provide a rich intellectual environment to foster the candidate's scientific development toward his goal of independent investigation. The proposed study will provide the applicant with the opportunity to study cellular activation and signal transduction pathways elicited by immune complexes in systemic lupus erythemus (SLE) serum. It has been known for many years that lupus patient's blood contains anti-dsDNA antibodies and DNA in complex. These immune complexes have been shown to be potent inducers of cytokine expression, such as IFN-alpha, which may play a part in the disease process. Toil-Like Receptors (TLRs) are pattern-recognition receptors that serve an important function in detecting pathogens and initiating inflammatory responses. Recently, TLR9 has been demonstrated to mediate responsiveness to unmethylated CpG DNA. Moreover, DNA fragments separated from immune complexes isolated from lupus patients was found to contain high frequencies of CpG dinucleotides. We hypothesized and found that TLR9 contributes in mediating responsiveness to the DNA component in immune complexes from lupus serum. To this end, this application has three specific aims: (1) To determine the domains of TLR9 involved in immune complex recognition and signaling. (2) To identify immune complex responsive cell types and determine the chemokine and cytokine gene expression profile in response to lupus serum. (3) To determine the mechanism of immune complex internalization.

描述（由申请人提供）：通过拟定的导师研究科学家发展奖（K01），申请人将利用其先前研究先天免疫的经验来增强其在细胞生物学、信号转导和自身免疫方面的技能。马萨诸塞州总医院安德鲁·D·卢斯特博士的实验室将提供丰富的智力环境，以促进候选人的科学发展，以实现其独立研究的目标。拟议的研究将为申请人提供研究系统性红斑狼疮（SLE）血清中免疫复合物引起的细胞激活和信号转导途径的机会。多年前人们就知道狼疮患者的血液中含有抗双链DNA抗体和DNA复合物。这些免疫复合物已被证明是细胞因子表达的有效诱导剂，例如 IFN-α，它可能在疾病过程中发挥作用。劳作样受体 (TLR) 是模式识别受体，在检测病原体和启动炎症反应方面发挥着重要作用。最近，TLR9 已被证明可以介导对未甲基化 CpG DNA 的反应。此外，从狼疮患者的免疫复合物中分离出来的 DNA 片段被发现含有高频率的 CpG 二核苷酸。我们假设并发现 TLR9 有助于介导对狼疮血清免疫复合物中 DNA 成分的反应。为此，本申请有三个具体目标：（1）确定TLR9参与免疫复合物识别和信号转导的结构域。 (2) 鉴定免疫复合物反应细胞类型并确定响应狼疮血清的趋化因子和细胞因子基因表达谱。 (3)确定免疫复合物内化的机制。