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: 7227096
• 负责人: TERRY K MEANS
• 金额: $ 11.72万
• 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/7227096
• 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）：在拟议的指导研究科学家发展奖（K01）的情况下，申请人将基于他先前研究先天免疫的经验，以提高他在细胞生物学，信号转导和自身免疫性方面的技能。马萨诸塞州综合医院的安德鲁·D·劳斯特（Andrew D.拟议的研究将为申请人提供研究细胞激活和信号转导途径的机会。众所周知，狼疮患者的血液中含有抗DSDNA抗体和复合物中的DNA。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，可能在疾病过程中起作用。辛苦的受体（TLR）是模式识别受体，在检测病原体和启动炎症反应方面起着重要功能。最近，TLR9已被证明可以介导对未甲基化CpG DNA的响应能力。此外，发现与从狼疮患者分离的免疫复合物分离的DNA片段被发现含有高频CpG二核苷酸。我们假设，发现TLR9在狼疮血清中免疫复合物中对DNA成分的响应有助于介导。为此，该应用具有三个特定的目的：（1）确定与免疫复合物识别和信号传导有关的TLR9域。 （2）鉴定免疫复杂的反应性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）确定免疫复杂内在化的机理。