Functional Dissection of Metabolic-Sensing Proline Hydroxylation Pathways
代谢传感脯氨酸羟基化途径的功能剖析
基本信息
- 批准号:10241993
- 负责人:
- 金额:$ 35.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAgingBiological ModelsCell SurvivalCell physiologyCellsData AnalysesDevelopmentDiseaseDissectionEnvironmentEnzymesFumaratesGoalsHydroxylationHydroxyprolineHypoxiaImmunoprecipitationIndividualInflammationIronLeadLinkMalignant NeoplasmsMass Spectrum AnalysisMediatingMetabolicMetabolic DiseasesMitochondriaOxygenPathway interactionsPost-Translational Protein ProcessingProcollagen-Proline DioxygenaseProlineProteinsProteomeProteomicsRegulationResearchRoleSiteSolid NeoplasmSuccinatesSystemTechnologyValidationalpha ketoglutaratecancer cellmulticatalytic endopeptidase complexnovelpreventprotein degradationprotein protein interactionproteostasisresponsesensorsuccesstool
项目摘要
Project Summary
Mounting evidence have demonstrated proline hydroxylation (Hyp) as a fundamental posttranslational
modification that are highly responsive to the changes in cellular metabolic environment. During cancer
development, rapid proliferation of cancer cells in solid tumors suffers from limited oxygen supply. The hypoxia
microenvironment prevents its hydroxyproline-dependent degradation of HIFα proteins and activates hypoxia-
response cellular pathways that promote cancer cell survival in hypoxia. In addition to oxygen, the regulatory
enzyme prolyl hydroxylases are also sensitive to the concentration of iron and key mitochondria metabolites
including succinate, fumarate and alpha-ketoglutarate, making the pathway a critical metabolic sensor in cells.
Extensive studies have demonstrated that proline hydroxylation of substrate proteins regulates protein-protein
interactions or substrate protein degradation. Despite of its important roles in cell physiology and success in
targeted analysis of individual substrates, system-wide characterization and functional quantification of the
pathway have been hindered by the lack effective tools and strategies for global site-specific identification of
proline hydroxylation targets. Our overall hypothesis and long-term goal is that systematic characterization of
“proline hydroxylome” through the development of functional proteomics approaches will lead to mechanistic
understanding of the novel Hyp-mediated metabolic regulations in development and diseases. To achieve this
goal, we have developed and applied an immunoprecipitation-assisted strategy for global identification of
proline hydroxylation targets. With this strategy, we will tackle the challenge of systematic discovery and
quantification of proline hydroxylation proteome. We will develop new quantitative proteomics workflows and
apply the strategies for the identification and validation of endogenous prolyl hydroxylase targets. Using
temporal dynamics analysis, we will also reveal the target proteins that are subject to Hyp-dependent protein
degradation. Integrated data analysis will reveal the regulatory enzyme of the novel Hyp substrates and
therefore enable confident validation as well as functional characterization. In addition to the target-specific
degradation, our preliminary proteomics analysis showed that proline hydroxylation may regulate global protein
homeostasis through the regulation of proteasome activities. We will develop endogenous model systems and
novel quantitative mass spectrometry technology to determine the functional significance of proline
hydroxylation on proteasome subunits and how such regulation affect global protein homeostasis. Overall, we
anticipate that the development and application of functional proteomics technology for system-wide analysis
of proline hydroxylation targets will reveal novel metabolic-sensing pathways and potentially lead to paradigm-
shifting concepts in the fields of cancer, metabolic diseases and aging.
项目摘要
越来越多的证据表明脯氨酸羟基化(Hyp)是一种重要的翻译后修饰酶,
这些修饰对细胞代谢环境的变化高度响应。在癌症
在癌症的发展过程中,实体瘤中癌细胞的快速增殖受到有限氧气供应的影响。缺氧
微环境阻止其HIFα蛋白的羟脯氨酸依赖性降解,并激活缺氧-
促进癌细胞在缺氧中存活的细胞反应途径。除了氧气,
脯氨酰羟化酶也对铁和关键线粒体代谢物的浓度敏感
包括琥珀酸、富马酸和α-酮戊二酸,使该途径成为细胞中的关键代谢传感器。
大量的研究表明,底物蛋白的脯氨酸羟基化调节蛋白质-蛋白质
相互作用或底物蛋白质降解。尽管它在细胞生理学中的重要作用和在细胞中的成功应用,
对单个底物进行有针对性的分析,
由于缺乏有效的工具和战略,无法在全球特定地点查明
脯氨酸羟基化靶点。我们的总体假设和长期目标是,
“脯氨酸羟化组”通过功能蛋白质组学方法的发展将导致机理
了解新的Hyp-mediated代谢调节在发展和疾病。实现这一
我们已经开发并应用了一种免疫沉淀辅助策略,用于全球识别
脯氨酸羟基化靶点。通过这一战略,我们将应对系统发现的挑战,
脯氨酸羟化蛋白质组的定量。我们将开发新的定量蛋白质组学工作流程,
应用内源性脯氨酰羟化酶靶标的鉴定和验证策略。使用
时间动力学分析,我们还将揭示受Hyp-dependent蛋白的靶蛋白
降解综合数据分析将揭示新型Hyp底物的调节酶,
因此能够进行可靠的验证以及功能表征。除了靶标特异性
我们初步的蛋白质组学分析表明,脯氨酸羟基化可能调节整体蛋白质
通过调节蛋白酶体的活性来维持体内平衡。我们将开发内生模型系统,
一种新的定量质谱技术来确定脯氨酸的功能意义
以及这种调节如何影响整体蛋白质稳态。总的来说,我们
预期功能蛋白质组学技术的发展和应用,
脯氨酸羟基化目标的研究将揭示新的代谢传感途径,并可能导致范式-
在癌症、代谢性疾病和衰老领域的概念转变。
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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Functional Dissection of Metabolic-Sensing Proline Hydroxylation Pathways
代谢传感脯氨酸羟基化途径的功能剖析
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