Cellular and Biologic Origins of CLL
CLL 的细胞和生物学起源
基本信息
- 批准号:8637334
- 负责人:
- 金额:$ 19.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-01-01 至 2015-12-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAntigen ReceptorsAntigensAwarenessB cell repertoireB-Cell DevelopmentB-Lymphocyte SubsetsB-LymphocytesBiologicalBiological MarkersBiologyBloodBone MarrowCell LineageCellsCellular ImmunityCharacteristicsChronic Lymphocytic LeukemiaClinicalCountryCountyDataDefectDerivation procedureDevelopmentDiagnosisDiagnosticDiseaseEtiologyExtended FamilyFc ReceptorFrequenciesGeneral PopulationGenesGeneticGoalsHeterogeneityHumanHuman BiologyHumoral ImmunitiesITAMImmuneImmune System DiseasesImmune systemImmunobiologyImmunocompromised HostImmunoglobulin Class SwitchingImmunoglobulin Somatic HypermutationIncidenceIndividualIndolentInterventionKnowledgeLesionLightLinkLymphoproliferative DisordersMalignant - descriptorMalignant NeoplasmsMediatingMemoryMemory B-LymphocyteMissionMolecularMutateOutcomePathogenesisPatientsPopulationPreventionPrevention strategyPrognostic FactorPropertyProteinsPublic HealthReceptor SignalingReceptors, Antigen, B-CellResearchResearch PersonnelRoleSignal PathwaySignal TransductionSomatic MutationSubgroupSurfaceSurface AntigensTestingTherapeuticTimeWorkagedaggressive therapybasedisorder preventionexperienceimmune functionimprovedinnovationleukemialymph nodesmembernovel strategiespublic health relevanceresponsetreatment strategyvaccination strategy
项目摘要
DESCRIPTION (provided by applicant): The normal cellular counterpart and etiology of B cell chronic lymphocytic leukemia (CLL), the most common leukemia in Western counties, still remains unknown. Fundamental to this knowledge gap is a limited awareness of the biological heterogeneity of human memory B cells. These issues are important challenges for determining CLL pathogenesis because without a more thorough understanding of this relationship, improving prevention, diagnostic, treatment, and vaccination strategies will continue to be difficult. The long-term goal is to understand the link between normal B cell development and the pathogenesis of CLL. The objective of this proposal is to analyze the molecular and functional features of newfound subpopulations in the human memory B cell repertoire to define the normal CLL-counterpart. The central hypothesis is that members of an extended family of Fc receptor-like (FCRL) molecules with immunoregulatory function mark subsets of memory B cells from which CLL derives. The rationale for the proposed research is that the discovery of the B cell subpopulation from which CLL arises will provide new appreciation of its pathogenesis and enable more informed approaches for treating this incurable lymphoproliferative disorder. Based on our preliminary data, this hypothesis will be tested in two specific aims: Aim 1 proposes to determine whether a memory B cell subset defined by FCRL expression molecularly resembles the pre-transformed CLL counterpart and Aim 2 will investigate the functional characteristics of FCRL expressing memory B cells. The contribution of this research will be significant because it will provide a comprehensive analysis of newfound memory B cell subpopulations to reveal for the first time the cellular origin(s) of CLL, help elucidate unexplored mechanisms involved in humoral immunity, and generate new knowledge for developing preventive and interventional strategies that link immune dysregulation and cancer. The proposed research is innovative because it overcomes previous less selective approaches by employing unique biomarkers of CLL possessing modulatory function that define previously unappreciated subsets in the human memory B cell repertoire resembling CLL cells. This novel strategy, will disclose molecular and functional features of these cells, shift our recognition of memory B cell diversity, assist in unearthing the CLL counterpart, and advance understanding of its pathogenesis. These outcomes are expected to have a positive impact because they will provide new avenues for researchers to develop preventative and therapeutic strategies for the treatment of CLL and other B cell disorders. Importantly, these studies should advance fundamental understanding of the dynamic interface between humoral immunity and the malignant transformation of B cells.
描述(由申请人提供):B细胞慢性淋巴细胞白血病(CLL)是西方国家最常见的白血病,其正常细胞对应物和病因仍然未知。这种知识差距的基础是对人类记忆B细胞生物异质性的有限认识。这些问题是确定CLL发病机制的重要挑战,因为如果不更彻底地了解这种关系,改善预防,诊断,治疗和疫苗接种策略将继续困难。长期目标是了解正常B细胞发育和CLL发病机制之间的联系。该建议的目的是分析人类记忆B细胞库中新发现的亚群的分子和功能特征,以定义正常的CLL对应物。中心假设是具有免疫调节功能的Fc受体样(FCRL)分子大家族成员标记CLL来源的记忆B细胞亚群。这项研究的基本原理是发现CLL产生的B细胞亚群,将为其发病机制提供新的认识,并使治疗这种无法治愈的淋巴组织增生性疾病的方法更加明智。基于我们的初步数据,这一假设将在两个特定的目标进行测试:目标1提出确定由FCRL表达定义的记忆B细胞亚群是否在分子上类似于预转化的CLL对应物,目标2将研究表达FCRL的记忆B细胞的功能特征。这项研究的贡献将是重要的,因为它将提供新发现的记忆B细胞亚群的全面分析,首次揭示CLL的细胞起源,帮助阐明体液免疫中未探索的机制,并为开发免疫失调和癌症的预防和干预策略提供新的知识。这项研究是创新的,因为它克服了以前的选择性较低的方法,采用独特的生物标志物的CLL具有调节功能,定义以前不受重视的子集在人类记忆B细胞库类似CLL细胞。这种新的策略,将揭示这些细胞的分子和功能特征,改变我们的记忆B细胞多样性的认识,协助发掘CLL对应物,并推进其发病机制的理解。这些结果预计将产生积极的影响,因为它们将为研究人员开发用于治疗CLL和其他B细胞疾病的预防和治疗策略提供新的途径。重要的是,这些研究应该推进体液免疫和B细胞恶性转化之间的动态界面的基本理解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RANDALL S DAVIS其他文献
RANDALL S DAVIS的其他文献
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{{ truncateString('RANDALL S DAVIS', 18)}}的其他基金
Modeling FCRL6 regulation and function in transgenic mice
转基因小鼠中 FCRL6 调控和功能的建模
- 批准号:
8534692 - 财政年份:2012
- 资助金额:
$ 19.18万 - 项目类别:
Modeling FCRL6 regulation and function in transgenic mice
转基因小鼠中 FCRL6 调控和功能的建模
- 批准号:
8226658 - 财政年份:2012
- 资助金额:
$ 19.18万 - 项目类别:
Validating a novel biomarker of clinical progression and survival in CLL
验证 CLL 临床进展和生存的新型生物标志物
- 批准号:
8322618 - 财政年份:2011
- 资助金额:
$ 19.18万 - 项目类别:
Validating a novel biomarker of clinical progression and survival in CLL
验证 CLL 临床进展和生存的新型生物标志物
- 批准号:
8509522 - 财政年份:2011
- 资助金额:
$ 19.18万 - 项目类别:
Validating a novel biomarker of clinical progression and survival in CLL
验证 CLL 临床进展和生存的新型生物标志物
- 批准号:
8177052 - 财政年份:2011
- 资助金额:
$ 19.18万 - 项目类别:
Biological Definition of FCRL Molecules in Malignancy
FCRL 分子在恶性肿瘤中的生物学定义
- 批准号:
7644436 - 财政年份:2008
- 资助金额:
$ 19.18万 - 项目类别:
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