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Caspase 8: A Novel Suppressor of Dendritic Cell-Mediated Autoimmunity

Caspase 8：树突状细胞介导的自身免疫的新型抑制剂

基本信息

批准号：
9248789
负责人：
Carla M Cuda
金额：
$ 11.93万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9248789
关键词：
Activated Lymphocyte Adverse effects Advisory Committees Age-Months Agonist Antigen-Antibody Complex Apoptosis Aspartic Acid Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity Belief CASP8 gene Career Mobility Caspase Inhibitor Cell Survival Cells Cellular biology Cessation of life Cysteine DNA Binding Data Dendritic Cells Dendritic cell activation Deposition Development Disease Disease remission Enzymes Exhibits Focus Groups Genetic Polymorphism Genetic Transcription Glomerulonephritis Goals Immune Immunologics Inflammation Inflammatory Injectable Interferon-alpha Interferons Interleukin-1 Interleukin-12 Kidney Lead Ligation Lymphatic Diseases Lymphoid Cell Measures Mediating Mentored Research Scientist Development Award Mentors Monitor Mus Myeloid Cells Necrosis Nucleic Acids Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Play Predisposition Process Production Proteinuria RIPK1 gene RIPK3 gene Receptor Signaling Relapse Research Research Proposals Rheumatism Role Serum Signal Transduction Splenomegaly Systemic Lupus Erythematosus TLR7 gene Therapeutic immunosuppression Training career cytokine ds-DNA effective therapy functional loss genetic variant inhibitor/antagonist knock-down member mortality novel overexpression paracrine prevent programs public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Uncovering novel mechanistic pathways involved in immune cell-mediated pathogenesis of autoimmune rheumatic diseases has been a consistent theme throughout my research career. Systemic lupus erythematosus (SLE) is a multi-organ and destructive autoimmune disease characterized by pathogenic autoantibodies. While it has been accepted that dendritic cells play an important role in the initiation of the disease, only recently have studies now implicated DCs as a major factor in the persistence of SLE. DCs from patients with SLE exhibit elevated expression of activation markers including co-stimulatory molecules and pro- inflammatory cytokines; however, the factors that are responsible for the aberrant activation is unknown. Caspase 8, an aspartic enzyme known to function in death receptor signaling, can initiate apoptosis and/or suppress necroptosis (through inhibition of RIPK1/3 signaling) in a multitude of cells. Preliminary studies show that mice lacking caspase 8 in DCs (CreCD11cCasp8flox/flox), exhibit a break in tolerance at as early as 2-3 months of age. CreCD11cCasp8flox/flox mice display splenomegaly, lymphadenopathy, dsDNA-reactive autoantibodies, glomerulonephritis, immune complex deposition in the kidney, exacerbated proteinuria levels, heightened amounts of serum pro-inflammatory cytokines (IL-12, IL-1¿, and IFN¿/¿)and early mortality. Loss of caspase 8 in DCs does not affect their survival, but they are highly activated, leading to elevated levels of activated lymphocytes in a paracrine manner. The increased activation potential of CreCD11cCasp8flox/flox DCs may be controlled by toll-like receptos 7 and 9 (TLR7/9) since caspase 8-deficient DCs display a hyper- responsiveness to TLR7/9 ligation with increased DNA binding activity of interferon regulatory factor (IRF). Additionally, blocking RIPK1 signaling dampens the TLR7/9-induced secretion of pro-inflammatory cytokines in caspase 8-deficient DCs. Collectively, these data suggest that intact caspase 8 signaling in DCs is crucial for preventing and/or limiting the hyper stimulation of DCs and induction of SLE-like disease. My progress and career advancement will be monitored throughout the five-year program by an Advisory Committee, which will include my mentor and four other members, and this group has already been instrumental in helping me develop my research proposal. My long-term career goal has been to build an academic research group focused on understanding immunologic mechanisms underlying the development of rheumatic diseases, with an emphasis on systemic lupus erythematosus (SLE). It is my belief that this proposal is an ideal training vehicle for a K01 Mentored Research Scientist Development Award, as I will become proficient in DC biology, as well as signal transduction, thereby developing my own niche in rheumatic disease as I begin to establish an independent academic career.

描述（由申请人提供）：揭示免疫细胞介导的自身免疫性风湿性疾病发病机制中的新机制途径一直是我研究生涯中的一个一致主题。系统性红斑狼疮（SLE）是一种以自身抗体为特征的多器官损害性自身免疫性疾病。虽然树突状细胞在疾病的发生中起着重要作用，但直到最近才有研究表明树突状细胞是SLE持续存在的主要因素。来自SLE患者的DC表现出活化标志物（包括共刺激分子和促炎细胞因子）的表达升高;然而，导致异常活化的因素尚不清楚。半胱天冬酶8是一种已知在死亡受体信号传导中起作用的天冬氨酸酶，可以在许多细胞中启动凋亡和/或抑制坏死性凋亡（通过抑制RIPK 1/3信号传导）。初步研究表明，在DC中缺乏半胱天冬酶8的小鼠（CreCD 11 cCasp 8 flox/flox）在早至2-3个月大时就表现出耐受性的破坏。CreCD 11 cCasp 8 flox/flox小鼠表现出脾肿大、淋巴结病、dsDNA反应性自身抗体、肾小球肾炎、肾脏中的免疫复合物沉积、蛋白尿水平加剧、血清促炎细胞因子（IL-12、IL-1和IFN）量升高和早期死亡。DCs中半胱天冬酶8的缺失不影响其存活，但它们高度活化，导致旁分泌方式活化淋巴细胞水平升高。CreCD 11 cCasp 8 flox/flox DC的增加的活化潜力可能受toll样受体7和9（TLR 7/9）控制，因为半胱天冬酶8缺陷型DC显示出对TLR 7/9连接的高反应性，并具有增加的干扰素调节因子（IRF）的DNA结合活性。此外，阻断RIPK 1信号传导抑制TLR 7/9诱导的caspase 8缺陷型DC中促炎细胞因子的分泌。总的来说，这些数据表明，DC中完整的半胱天冬酶8信号传导对于预防和/或限制DC的过度刺激和SLE样疾病的诱导至关重要。我的进步和职业发展将在整个五年计划中由一个咨询委员会进行监测，该委员会将包括我的导师和其他四名成员，这个小组已经帮助我制定了我的研究计划。我的长期职业目标是建立一个学术研究小组，专注于了解风湿性疾病发展的免疫机制，重点是系统性红斑狼疮（SLE）。我相信，这个建议是一个理想的培训工具K 01指导研究科学家发展奖，因为我将成为精通DC生物学，以及信号转导，从而发展我自己的利基在风湿性疾病，因为我开始建立一个独立的学术生涯。