Analyzing protein homeostasis pathways in multiple myeloma stem-like cells
分析多发性骨髓瘤干细胞样细胞中的蛋白质稳态途径
基本信息
- 批准号:10520036
- 负责人:
- 金额:$ 36.31万
- 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:2014-07-02 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAntibodiesAutologous Stem Cell TransplantationAutophagocytosisB lymphoid malignancyB-LymphocytesBindingBiochemicalBiological AssayBlood VesselsBone MarrowBone SurfaceCatabolismCell SeparationCell SurvivalCellsClinicalClinical TreatmentComplexCytolysisDNA Sequence AlterationDependenceDeubiquitinationDevelopmentDrug resistanceEndotheliumFamilyFamily memberGene Expression ProfilingGene SilencingGoalsHeterogeneityHigh Dose ChemotherapyHumanLinkMalignant NeoplasmsMass Spectrum AnalysisMediatingMethodsMolecularMultiple MyelomaNeoplasmsNeoplastic Plasma CellPathogenesisPathologyPathway interactionsPatientsPlasmaPlayPredispositionProcessProliferatingProteasome InhibitionProteasome InhibitorProtein BiosynthesisProtein FamilyProteinsRecurrenceRecurrent tumorRefractoryRelapseReportingResistanceResistance developmentRoleSamplingSignal PathwaySignal TransductionStressSystemTRIM MotifTestingTracerUbiquitinXenograft procedurebonecell growthchemotherapyclinically relevantimprovedimproved outcomein vivoinhibitormembermisfolded proteinmouse modelmulticatalytic endopeptidase complexnew therapeutic targetnovelpre-clinicalpreventprotein aggregationprotein complexprotein degradationprotein functionprotein protein interactionproteostasisproteotoxicityreceptorscreeningstemstem cell survivalstem cellsstem-like cellsurvival outcometherapy resistanttreatment responseubiquitin isopeptidase
项目摘要
Abstract:
Multiple myeloma (MM) is an incurable B cell malignancy that is characterized by the growth of neoplastic
plasma cells within the bone marrow microenvironment. Despite progress in the clinical treatment of MM,
including the use of high-dose chemotherapy and autologous stem cell transplantation, a considerable
proportion of patients develop resistance and become refractory to therapies. Drug resistance in MM is
enabled by evolving genomic alterations as well as by contributions from stromal components in the bone
marrow microenvironment. Specifically, the bone marrow provides a protective niche for slowly cycling/
quiescent stem-like MM cells that are not killed by chemotherapies. We have discovered sub-populations of
MM stem-like cells that preferentially localize to osteoblastic niches of the bone marrow. Gene expression
profiling revealed that a novel tripartite motif factor, TRIM44, is upregulated in MM stem-like cells isolated from
the osteoblastic niche. TRIM family proteins function as autophagy-regulatory receptors and TRIM44 gene
silencing decreases autophagy. In this project, we will investigate roles for TRIM44 and its links to protein
homeostasis control during MM initiation, progression and resistance to therapy. Our working hypothesis is that
TRIM44 plays integral roles in promoting quiescent MM stem cell survival within the bone marrow niche by
regulating pathways involved in proteotoxic stress. Furthermore, we propose that targeting TRIM44 or its
interacting proteins will result in diminished MM survival and improved outcome in response to therapy. To test
this hypothesis, we will (i) analyze signaling pathways regulated by TRIM44 and determine how components of
these pathways promote cell survival under proteotoxic stress; (ii) characterize novel substrates (from a recent
mass spectrometry screen) that selectively bind to TRIM44 and determine the functional significance of these
interactions in primary MM cells; and (iii) delineate the clinical relevance of these TRIM44-dependent pathways
in MM pathogenesis and relapse using xenograft mouse models. Our long-term goal is to selectively inhibit
TRIM44-dependent signaling pathways to benefit patients by reducing MM progression and/or blocking tumor
recurrence after therapy.
摘要:
多发性骨髓瘤(MM)是一种无法治愈的B细胞恶性肿瘤,其特征在于肿瘤性细胞的生长。
骨髓微环境中的浆细胞。尽管MM的临床治疗取得了进展,
包括使用大剂量化疗和自体干细胞移植,
部分患者产生耐药性并对治疗变得难治。MM的耐药性是
通过进化的基因组改变以及骨中基质成分的贡献,
骨髓微环境具体地说,骨髓提供了一个保护性的小生境,
不被化疗杀死的静止干细胞样MM细胞。我们发现了
优先定位于骨髓成骨细胞龛的MM干细胞样细胞。基因表达
分析显示,一种新的三联基序因子TRIM 44在从骨髓瘤中分离的MM干细胞样细胞中上调,
成骨细胞龛自噬调节受体TRIM家族蛋白与TRIM 44基因
沉默减少自噬。在这个项目中,我们将研究TRIM 44的作用及其与蛋白质的联系。
MM开始、进展和对治疗抵抗期间的稳态控制。我们的假设是
TRIM 44在促进静止MM干细胞在骨髓小生境内存活中起着不可或缺的作用,
参与蛋白毒性应激的调节途径。此外,我们建议,针对TRIM 44或其
相互作用的蛋白质将导致MM存活率降低和对治疗应答的结果改善。测试
根据这一假设,我们将(i)分析TRIM 44调控的信号通路,并确定TRIM 44的组分如何影响细胞的功能。
这些途径促进蛋白毒性应激下的细胞存活;(ii)表征新底物(来自最近的
质谱筛选),其选择性地结合TRIM 44并确定这些的功能意义
在原代MM细胞中的相互作用;和(iii)描绘这些TRIM 44依赖性途径的临床相关性
在MM发病机制和复发中的作用。我们的长期目标是有选择地抑制
TRIM 44依赖性信号通路通过减少MM进展和/或阻断肿瘤而使患者受益
治疗后复发。
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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Nami McCarty其他文献
Nami McCarty的其他文献
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{{ truncateString('Nami McCarty', 18)}}的其他基金
Delineating roles for a novel tri-protein complex (TRIM44) in the multiple myeloma stem cell niche
描述新型三蛋白复合物 (TRIM44) 在多发性骨髓瘤干细胞生态位中的作用
- 批准号:
9306792 - 财政年份:2016
- 资助金额:
$ 36.31万 - 项目类别:
Targeting Stem-Cell Dependent Drug Resistance in Human MCL
靶向人类 MCL 中的干细胞依赖性耐药性
- 批准号:
9263689 - 财政年份:2014
- 资助金额:
$ 36.31万 - 项目类别:
Targeting Stem-Cell Dependent Drug Resistance in Human MCL
靶向人类 MCL 中的干细胞依赖性耐药性
- 批准号:
8884564 - 财政年份:2014
- 资助金额:
$ 36.31万 - 项目类别:
Targeting Stem-Cell Dependent Drug Resistance in Human MCL
靶向人类 MCL 中的干细胞依赖性耐药性
- 批准号:
8760722 - 财政年份:2014
- 资助金额:
$ 36.31万 - 项目类别:
Analyzing protein homeostasis pathways in multiple myeloma stem-like cells
分析多发性骨髓瘤干细胞样细胞中的蛋白质稳态途径
- 批准号:
10308685 - 财政年份:2014
- 资助金额:
$ 36.31万 - 项目类别:
Characterizing Clonogenic Populations in Mantle Cell Lymphoma
套细胞淋巴瘤克隆形成群体的特征
- 批准号:
7992452 - 财政年份:2009
- 资助金额:
$ 36.31万 - 项目类别:
Characterizing Clonogenic Populations in Mantle Cell Lymphoma
套细胞淋巴瘤克隆形成群体的特征
- 批准号:
7788035 - 财政年份:2009
- 资助金额:
$ 36.31万 - 项目类别:
Identification and characterization of molecules important in the immune system
免疫系统中重要分子的鉴定和表征
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$ 36.31万 - 项目类别:
Identification and characterization of molecules important in the immune system
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7126607 - 财政年份:2006
- 资助金额:
$ 36.31万 - 项目类别:
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