Immunoglobulin Structure, Stability and Aging
免疫球蛋白结构、稳定性和老化
基本信息
- 批准号:7666819
- 负责人:
- 金额:$ 33.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-04-15 至 2011-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAgingAlzheimer&aposs DiseaseAmyloidAmyloidosisAmyotrophic Lateral SclerosisAnimal ModelAntibodiesArgonB-LymphocytesBiologicalBiological AssayCell modelCellsCentral Nervous System DiseasesCollectionComplementDepositionDiagnosisDiagnosticDiseaseDistantEffectivenessEnergy TransferEnvironmentEventFluorescence MicroscopyFrequenciesFunctional disorderGenesGenetic CrossesGrantGreekHandHistologyHumanHuntington DiseaseImmune responseIn VitroInclusion BodiesLeadLibrariesLightLight Chain Deposition DiseaseLight-Chain ImmunoglobulinsLocationMediatingMicroscopyModalityModelingMolecularMolecular ConformationMusMutationNatureOrganOrgan failureParkinson DiseasePathologyPathway interactionsPatientsPeptidesPricePrion DiseasesPrionsPropertyProteinsReactionRecruitment ActivityResolutionSeedsSomatic MutationSpecificitySurfaceSurveysSystemic diseaseTestingTransgenic MiceWorkamyloid formationbasedesigneffective therapyefficacy testingextracellularfibrillogenesisimmunoglobulin structurein vivoinhibitor/antagonistinsightinterestmouse modelmutantpolymerizationprimary amyloidosis of light chain typeprion-likeprogramsprotein aggregationprotein aminoacid sequenceresearch studytherapy developmenttool
项目摘要
DESCRIPTION (provided by applicant): Light chain amyloidosis (AL) is the most common systemic protein aggregation disease. It is not only debilitating and often fatal, but also difficult to diagnose, because of the variety of affected internal organs. Its molecular cause is a conformational change in specific immunoglobulin light chains (LCs), due to somatic mutations accumulated during the course of immune responses. Specific mutations cause the LCs to polymerize into fibrils that then deposit as plaques. The disease has no direct and effective treatment and the development of one is complicated by the lack of an animal model. This renewal application seeks to build upon the in vitro fibrillogenesis reactions, cellular models and an inhibitory peptide that were developed in the first grant period. These tools will be used to determine the molecular specificity inherent in LC fibrillogenesis reactions. Since we previously showed that some amyloidogenic LC are not secreted and form intracellular inclusion bodies, our first Aim is to test multiple amyloidogenic LCs and determine which sequences are compatible with secretion and which LCs form inclusion bodies. One type of intracellular aggregate, termed aggresome, is of particular interest, because it is likely fibrillar, based on its sensitivity to the inhibitory peptide. This survey of LCs is important in characterizing the intracellular and extracellular pathways of LC amyloid formation. Aim2 will pursue our observations that some LCs can form two distinct types of fibrils, and on the other hand, that LC fibrils can initiate polymerization of other, more distant proteins. A library of mutants will be used to determine the requirements for formation of fibrils from either the oxidized or the reduced LC. We will next test the hypothesis that the unfolding of proteins with Greek key fold (such as LC, p2m, TTR or SOD1) is constrained and thereby leads to a common conformation that can give rise to similar fibrils. This hypothesis will be tested in two ways: seeding of each of these proteins with fibrils of another, and determining the sensitivity of different fibrils to the inhibitory peptide. The similarity uncovered in vitro will then be applied to the intracellular environment by determining the degree of co-aggregation of Greek key proteins. Aim 3 is to use mice transgenic for one amyloidogenic LC and assess their suitability as an animal model for AL by manipulating them genetically and immunologically so as to form amyloid deposits. If successful, this model will be used to test the efficacy of the peptide that specifically blocks fibrillogenesis of Greek Key proteins as a potential treatment modality. Relevance: This project continues to investigate the molecular mechanisms that underlie light chain amyloidosis, a fatal protein aggregation disease where deposits of antibody light chains cause plaques and lead to dysfunction of vital organs.
描述(由申请人提供):轻链淀粉样变性(AL)是最常见的全身蛋白质聚集疾病。由于受影响的内脏多种多样,它不仅使人衰弱,而且经常致命,而且很难诊断。它的分子原因是由于在免疫反应过程中积累的体细胞突变,特异性免疫球蛋白光链(LCS)的构象变化。特异性突变导致LCS聚合成原纤维,然后沉积为斑块。该疾病没有直接有效的治疗,并且由于缺乏动物模型而变得复杂。该更新应用旨在建立在第一个赠款时期开发的体外原始生成反应,细胞模型和抑制性肽的基础上。这些工具将用于确定LC原纤维发生反应中固有的分子特异性。由于我们以前表明某些淀粉样蛋白生成的LC不是分泌的,并且会形成细胞内夹杂物,因此我们的第一个目的是测试多个淀粉样蛋白生成的LC,并确定哪些序列与分泌兼容,哪些LCS形成包容体。一种类型的细胞内聚集体(称为杂种)特别令人感兴趣,因为它可能是基于对抑制性肽的敏感性的原纤维。这项对LCS的调查对于表征LC淀粉样蛋白形成的细胞内和细胞外途径很重要。 AIM2将追求我们的观察,即某些LC可以形成两种不同类型的原纤维,另一方面,LC原纤维可以启动其他更遥远的蛋白质的聚合。突变体库将用于确定从氧化或还原Lc形成原纤维的要求。接下来,我们将测试蛋白质与希腊钥匙褶皱的展开(例如LC,P2M,TTR或SOD1)的假设受到限制,从而导致一种常见的构象,可以引起类似的原纤维。该假设将通过两种方式进行检验:每种蛋白质与另一个原纤维的播种,并确定不同原纤维对抑制性肽的敏感性。然后,通过确定希腊钥匙蛋白的共聚集程度,将在体外发现的相似性应用于细胞内环境。 AIM 3是将小鼠转基因用于一种淀粉样蛋白生成LC,并通过在遗传和免疫学上操纵它们作为AL的适用性,以形成淀粉样蛋白沉积物。如果成功,该模型将用于测试肽的功效,该肽特异性地阻断了希腊钥匙蛋白作为潜在治疗方式的原纤维生成。相关性:该项目继续研究光链淀粉样变性(一种致命的蛋白质聚集疾病)的分子机制,其中抗体光链沉积会导致斑块并导致活力器官功能障碍。
项目成果
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