Role of DAF in the Complement Cascade

DAF 在补体级联中的作用

• 批准号: 7891024
• 负责人: MELVIN EDWARD MEDOF
• 金额: $ 7.26万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891024
• 关键词: Active Sites; Antigens; Autoantibodies; Autoimmune Process; Autologous; CD55 Antigens; Cells; Complement; Complement 3 Convertase; Complement Activation; Complement Factor D; Disease; Experimental Autoimmune Encephalomyelitis; Experimental Models; Immune; Inflammatory; Injury; Knock-out; Knockout Mice; Ligands; Lung diseases; Lymphocyte Function; Maps; Mediating; Membrane; Methods; Molecular Mechanisms of Action; Mus; Mutagenesis; Neoplasms; Pathogenesis; Pathway interactions; Physiological; Process; Proteins; Recombinants; Regulation; Research; Role; Site; T-Lymphocyte; Transgenic Mice; Work; base; cell injury; design; in vivo; inhibitor/antagonist; insight; mouse model; novel strategies; protein expression; transcription factor

DESCRIPTION (provided by applicant): Decay accelerating factor (DAF) is a 70 kDa intrinsic membrane regulator that protects self cells from autologous complement-mediated injury. It functions by decaying the C3 central convertases (C4b2a and C3bBb), a process which determines whether complement activation aborts or proceeds. Through previous mutagenesis studies and NMR structural analyses, we have provisionally mapped DAF's active site(s). In other work, we have prepared Daf knockout mice and have begun to characterize DAF's physiological importance in different autoimmune/inflammatory states. Our proposed research is designed to provide insights into several unresolved questions concerning DAF's function. Aim 1 focuses on precisely characterizing DAF's interface with the C3 convertases and defining its molecular mechanism of action. This should provide a basis not only for understanding DAF's function but for unraveling the actions of other C3 convertase regulators. Aim 2 focuses on further clarifying DAF's overall physiological function in vivo. This should shed important insights into the pathogeneses of a number of disorders as well as new information on immune regulation and immune effector function. Aim 3 focuses on a) characterizing the transcriptional mechanisms controlling expression levels of DAF and other intrinsic regulators and b) targeting exogenous recombinant DAF derivatives to specific sites in vivo. This latter work is relevant not only to autoimmune/inflammatory disorders but potentially also to neoplasia. New findings concerning pharmacological manipulation of the proteins' expression levels via transcriptional mechanisms could open the way to new approaches to therapy.

描述（由申请人提供）：衰减加速因子（DAF）是一种70 kDa的内在膜调节剂，可保护自体细胞免受自体补体介导的损伤。它通过衰减C3中心转化酶（C4B2A和C3BBB）来发挥作用，该过程确定补体激活是否流产还是进行。通过以前的诱变研究和NMR结构分析，我们已经临时映射了DAF的活性位点。在其他工作中，我们已经准备了DAF淘汰小鼠，并开始表征DAF在不同自身免疫/炎症状态下的生理重要性。 我们提出的研究旨在提供有关DAF功能的几个未解决问题的见解。 AIM 1的重点是精确表征DAF与C3转化酶的界面，并定义其分子作用机理。这不仅应该为理解DAF的功能提供基础，还为揭示其他C3转化酶调节剂的行为。 AIM 2专注于进一步阐明DAF在体内的总体生理功能。这应该为多种疾病的病原体以及有关免疫调节和免疫效应子功能的新信息提供重要的见解。 AIM 3的重点是a）表征控制DAF和其他内在调节剂表达水平的转录机制，b）靶向外源重组DAF衍生物对体内特定位点的靶向。后一种工作不仅与自身免疫/炎症性疾病有关，而且可能与肿瘤疾病有关。关于通过转录机制对蛋白质表达水平进行药理学操纵的新发现，可以为新的治疗方法开辟道路。

项目成果

Absence of signaling into CD4⁺ cells via C3aR and C5aR enables autoinductive TGF-β1 signaling and induction of Foxp3⁺ regulatory T cells.

• DOI: 10.1038/ni.2499
• 发表时间: 2013-02
• 期刊: Nature immunology
• 影响因子: 30.5

Normal polymorphic variations and transcription of the decay accelerating factor gene in paroxysmal nocturnal hemoglobinuria cells.

阵发性睡眠性血红蛋白尿细胞中腐烂加速因子基因的正常多态性变异和转录。

• DOI: 10.1073/pnas.85.3.880
• 发表时间: 1988
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Stafford,HA;Tykocinski,ML;Lublin,DM;Holers,VM;Rosse,WF;Atkinson,JP;Medof,ME
• 通讯作者: Medof,ME

Decay-accelerating factor modulates induction of T cell immunity.

• DOI: 10.1084/jem.20041967
• 发表时间: 2005-05-16
• 期刊: The Journal of experimental medicine
• 作者: Heeger PS;Lalli PN;Lin F;Valujskikh A;Liu J;Muqim N;Xu Y;Medof ME
• 通讯作者: Medof ME

Conservation in decay accelerating factor (DAF) structure among primates.

• DOI: 10.1016/s0145-305x(00)00026-4
• 发表时间: 2000-12
• 期刊: Developmental and comparative immunology
• 影响因子: 2.9
• 作者: L. Kuttner-Kondo;V. Subramanian;J. Atkinson;J. Yu;M. Medof

Effect of glycoinositolphospholipid anchor lipid groups on functional properties of decay-accelerating factor protein in cells.

糖肌醇磷脂锚定脂质基团对细胞内加速腐烂因子蛋白功能特性的影响。

• 发表时间: 1992
• 期刊: The Journal of biological chemistry
• 作者: Walter,EI;Ratnoff,WD;Long,KE;Kazura,JW;Medof,ME
• 通讯作者: Medof,ME