Regulation of GDF11 by extracellular mechanisms
细胞外机制对 GDF11 的调节
基本信息
- 批准号:10689719
- 负责人:
- 金额:$ 54.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAgeAgingAnimalsBindingBiochemicalBiologicalBiological ProcessBuffersCentral Nervous SystemClinicalClinical TrialsComplexCoupledCuesDevelopmentEngineeringErythrocytesExtracellular ProteinFamilyFamily memberFollistatinGDF11 geneGDF8 geneGoalsGrowth FactorHeartHuman BiologyIn VitroLaboratoriesLigand BindingLigandsMeasurementMediatorModelingMolecularN-terminalPeptide HydrolasesProcessProductionProtease DomainPublishingRationalizationReagentReceptor SignalingRegulationRejuvenationRoleSerumSignal TransductionSignaling MoleculeSystemTestingTransforming Growth Factor betaWorkage relatedagedantagonistbiological systemscell growth regulationdesignexperimental studyextracellulargraspin vitro activityin vivoin vivo evaluationinterestmorphogensmuscle formnovelrestorationtool
项目摘要
Project Summary: Growth and Differentiation Factor 11 (GDF11) and GDF8 are two closely related molecules
of the larger TGFβ superfamily. While GDF8 is well known for its role in the regulation of muscle mass, evidence
is now emerging that implicates GDF11 as a factor that has beneficial effects on multiple biological systems.
Both GDF11 and GDF8 are tightly regulated by multiple mechanisms. Each ligand is made as a precursor with
an N-terminal prodomain that remains noncovalently bound to the mature, keeping the signaling component
latent until activated by Tolloid-like proteases. In addition, extracellular antagonists such as Follistatin and GASP
bind and block ligand signaling. We propose that GDF11 and GDF8 are present in the serum in multiple activity
states ranging from a latent form to an activated form. However, studies that investigate how the different activity
states are differentially regulated are limited. We rationalize that a better understanding of these mechanisms
will facilitate efforts to understand the systemic role of GDF11 and GDF8 in human biology and the aging process.
To achieve this objective, we will use a combination of biochemical and molecular approaches coupled with in
vitro and in vivo experiments. Our proposal is centered on three specific aims where we will (1) test the
hypothesis that GDF11 and GDF8 exists in multiple ‘activity’ states that regulate a transition from a latent state
to an active state, (2) test the hypothesis that the ‘net’ GDF11/GDF8 activity in serum decreases with age, and
(3) test the hypothesis that GDF11 signaling and its regulation/extracellular antagonism can be decoupled.
Collectively, these aims will provide a better understanding of the mechanisms of extracellular regulation of
GDF11 and GDF8 and how these potentially change during the aging process. Furthermore, we expect to
produce novel GDF11 and GDF8 molecules that can be used as tools to further probe the mechanisms
associated with GDF11 and aging, and can also be used to restore youthful levels of GDF11 in aged animals.
项目概述:生长与分化因子11 (Growth and Differentiation Factor 11, GDF11)和GDF8是两个关系密切的分子
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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THOMAS B THOMPSON其他文献
THOMAS B THOMPSON的其他文献
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Structural/functional characterization of TGFβ superfamily signaling and regulation
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- 批准号:
10335177 - 财政年份:2020
- 资助金额:
$ 54.1万 - 项目类别:
Regulation of GDF11 by extracellular mechanisms
细胞外机制对 GDF11 的调节
- 批准号:
10252072 - 财政年份:2020
- 资助金额:
$ 54.1万 - 项目类别:
Regulation of GDF11 by extracellular mechanisms
细胞外机制对 GDF11 的调节
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10206827 - 财政年份:2020
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$ 54.1万 - 项目类别:
Structural/functional characterization of TGFβ superfamily signaling and regulation
TGFβ 超家族信号传导和调节的结构/功能表征
- 批准号:
10551878 - 财政年份:2020
- 资助金额:
$ 54.1万 - 项目类别:
Regulation of GDF11 by extracellular mechanisms
细胞外机制对 GDF11 的调节
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$ 54.1万 - 项目类别:
Structural/functional characterization of TGFβ superfamily signaling and regulation
TGFβ 超家族信号传导和调节的结构/功能表征
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10094061 - 财政年份:2020
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