Role of DAF in the Complement Cascade
DAF 在补体级联中的作用
基本信息
- 批准号:7891024
- 负责人:
- 金额:$ 7.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Active SitesAntigensAutoantibodiesAutoimmune ProcessAutologousCD55 AntigensCellsComplementComplement 3 ConvertaseComplement ActivationComplement Factor DDiseaseExperimental Autoimmune EncephalomyelitisExperimental ModelsImmuneInflammatoryInjuryKnock-outKnockout MiceLigandsLung diseasesLymphocyte FunctionMapsMediatingMembraneMethodsMolecular Mechanisms of ActionMusMutagenesisNeoplasmsPathogenesisPathway interactionsPhysiologicalProcessProteinsRecombinantsRegulationResearchRoleSiteT-LymphocyteTransgenic MiceWorkbasecell injurydesignin vivoinhibitor/antagonistinsightmouse modelnovel strategiesprotein expressiontranscription factor
项目摘要
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):衰变加速因子(Decay Accelerating Factor,ERF)是一种70 kDa的内在膜调节因子,可保护自身细胞免受自体补体介导的损伤。它通过衰变C3中心转化酶(C4 b2 a和C3 bBb)发挥作用,这是一个决定补体激活中止或继续的过程。通过先前的诱变研究和NMR结构分析,我们已经初步定位了Escherichia coli的活性位点。在其他工作中,我们已经制备了Daf敲除小鼠,并开始表征Daf在不同自身免疫/炎症状态中的生理重要性。
我们提出的研究目的是提供一些尚未解决的问题,关于神经元的功能的见解。目标1的重点是精确地表征C3转化酶的界面,并定义其分子作用机制。这不仅为理解C3转化酶的功能提供了基础,也为阐明其他C3转化酶调节剂的作用提供了基础。目的2:进一步阐明β-淀粉样蛋白在体内的整体生理功能。这将为许多疾病的发病机制以及免疫调节和免疫效应功能提供重要的见解。目的3集中于a)表征控制β-内酰胺酶和其它内在调节剂的表达水平的转录机制和B)将外源重组β-内酰胺酶衍生物靶向至体内特定位点。后一项工作不仅与自身免疫性/炎症性疾病相关,而且可能与肿瘤形成相关。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能为新的治疗方法开辟道路。
项目成果
期刊论文数量(34)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 影响因子:30.5
- 作者:
- 通讯作者:
Decay-accelerating factor modulates induction of T cell immunity.
- DOI:10.1084/jem.20041967
- 发表时间:2005-05-16
- 期刊:
- 影响因子:0
- 作者:Heeger PS;Lalli PN;Lin F;Valujskikh A;Liu J;Muqim N;Xu Y;Medof ME
- 通讯作者:Medof ME
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:
- 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
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。
- DOI:
- 发表时间:1992
- 期刊:
- 影响因子:0
- 作者:Walter,EI;Ratnoff,WD;Long,KE;Kazura,JW;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:
- 影响因子:2.9
- 作者:L. Kuttner-Kondo;V. Subramanian;J. Atkinson;J. Yu;M. Medof
- 通讯作者:L. Kuttner-Kondo;V. Subramanian;J. Atkinson;J. Yu;M. Medof
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MELVIN EDWARD MEDOF的其他文献
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{{ truncateString('MELVIN EDWARD MEDOF', 18)}}的其他基金
Optimizing mesenchymal stem cell and Treg immunosuppression for controlling SLE
优化间充质干细胞和 Treg 免疫抑制以控制 SLE
- 批准号:
8964783 - 财政年份:2015
- 资助金额:
$ 7.26万 - 项目类别:
Optimizing mesenchymal stem cell and Treg immunosuppression for controlling SLE
优化间充质干细胞和 Treg 免疫抑制以控制 SLE
- 批准号:
9314221 - 财政年份:2015
- 资助金额:
$ 7.26万 - 项目类别:
Optimizing mesenchymal stem cell and Treg immunosuppression for controlling SLE
优化间充质干细胞和 Treg 免疫抑制以控制 SLE
- 批准号:
9105570 - 财政年份:2015
- 资助金额:
$ 7.26万 - 项目类别:
Local Complement Synthesis and Signaling by Endothelial and Inflammatory Cells
内皮细胞和炎症细胞的局部补体合成和信号传导
- 批准号:
8373385 - 财政年份:2012
- 资助金额:
$ 7.26万 - 项目类别:
Local Complement Synthesis and Signaling by Endothelial and Inflammatory Cells
内皮细胞和炎症细胞的局部补体合成和信号传导
- 批准号:
8517802 - 财政年份:2012
- 资助金额:
$ 7.26万 - 项目类别:
Local Complement Synthesis and Signaling by Endothelial and Inflammatory Cells
内皮细胞和炎症细胞的局部补体合成和信号传导
- 批准号:
8678990 - 财政年份:2012
- 资助金额:
$ 7.26万 - 项目类别:
Pathogenic Mechanisms Underlying Diabetic Retinopathy
糖尿病视网膜病变的发病机制
- 批准号:
6904443 - 财政年份:2004
- 资助金额:
$ 7.26万 - 项目类别:
Pathogenic Mechanisms Underlying Diabetic Retinopathy
糖尿病视网膜病变的发病机制
- 批准号:
7287402 - 财政年份:2004
- 资助金额:
$ 7.26万 - 项目类别:
Pathogenic Mechanisms Underlying Diabetic Retinopathy
糖尿病视网膜病变的发病机制
- 批准号:
6762097 - 财政年份:2004
- 资助金额:
$ 7.26万 - 项目类别:
Pathogenic Mechanisms Underlying Diabetic Retinopathy
糖尿病视网膜病变的发病机制
- 批准号:
7070529 - 财政年份:2004
- 资助金额:
$ 7.26万 - 项目类别:
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