Validation of the Estrogen Related Receptor as a therapeutic target in cancer
Validation of the Estrogen Related Receptor as a therapeutic target in cancer
批准号:
8012324
负责人:
Donald P McDonnell
金额:
$8.93万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-02-04 至 2010-04-30
关键词:
AddressAdoptedAffinityAgonistAgreementAnimal ModelAnimal WelfareBibliographyBiogenesisBiologyBoxingBreast Cancer CellCell LineCell RespirationCell modelCellsCitric Acid CycleComplexCountryDataData SetDisease OutcomeERBB2 geneEngineeringEnvironmentEnvironmental ImpactEnzymesEpithelial CellsEquipmentEstrogen AntagonistsEstrogen Receptor ModulatorsEstrogen ReceptorsEstrogensFamilyFunctional disorderGene ActivationGene ExpressionGene Expression ProfileGene TargetingGenerationsGenesGoalsGrantHumanIACUCImpact evaluationIntentionInternationalLeadLeftLigand BindingLigandsLinkMCF7 cellMalignant NeoplasmsMammary NeoplasmsMammary glandMetabolic PathwayMetabolismMitochondriaModelingMolecular ConformationNuclear ReceptorsOrphanOutcomePaperPathway interactionsPeptidesPharmaceutical PreparationsPharmacologic SubstancePrincipal InvestigatorProcessProteinsPublished CommentPublishingResearchResearch Ethics CommitteesResearch PersonnelResourcesRoleSignal TransductionSmall Interfering RNAStreamSuggestionSurfaceTechnologyTestingTimeTumor PathologyValidationVertebratesWorkabstractingbasecofactorcombinatorialestrogen-related receptorexpirationfatty acid oxidationhuman subjectmalignant breast neoplasmmeetingsmutantoutcome forecastoverexpressionprogramsreceptorreceptor functionresearch studyresponsesuccesstherapeutic targettumor
中文摘要
核受体超家族的几个成员
转录因子与线粒体功能的生物发生和/或调节有关。
更具体地说,包括我们自己的实验室在内的许多实验室最近的工作表明,
核受体雌激素受体相关受体-a(ERRa)调节大多数
核编码基因参与脂肪酸β-氧化和氧化磷酸化。此外,本发明还提供了一种方法,
我们现在有令人信服的数据表明,这种受体参与了细胞的正调控,
TCA循环,类固醇生成,胆汁酸代谢,血管生成,己糖磷酸分流,
线粒体氨基酸转运,并且它也负调节线粒体氨基酸转运中的限速步骤。
糖酵解途径ERRa活性与线粒体功能的联系重新激发了人们对
该受体亚家族作为癌症、代谢疾病和线粒体疾病的治疗靶点,
营养不良由于它们与经典雌激素受体(ER α和ER β)的结构相似,
长期以来一直认为ERRs作为雌激素反应性的调节剂发挥作用。现在
然而,与ER信号无关的活动似乎是ERR的一个同样重要的方面
生物学在这项研究中,一系列的新技术,这已经在我们的实验室开发,将
用于(a)定义ERRa在肝脏生物学中的特定作用和(B)确定ERRa是否
不同受体-辅因子复合物的形成与不同的生物学结果相关。
这项工作将提供对这种受体亚类的生理作用的理解,
建立一个科学框架,在此基础上建立旨在发展的发现计划,
组织/过程选择性ERR调节剂。这些目标将在完成
以下具体目标:目标1:使用定制的ERRa在肝脏中的生理作用的定义
目标2:ERRa信号传导的分子组分的鉴定
目的3:评价辅因子对ERRa转录活性的影响目的4:
通过ERRa检查差异性因子募集的生物学后果:
共激活因子假说
英文摘要
Several members of the nuclear receptor superfamily of
transcription factors have been implicated in the biogenesis and/or regulation of mitochondrial function.
More specifically, recent work from many laboratories, including our own, has indicated that the orphan
nuclear receptor Estrogen Receptor- Related Receptor-a (ERRa) regulates the expression of most of
the nuclear encoded genes involved in fatty acid (3-oxidation and oxidative phosphorylation. In addition,
we now have compelling data that indicate that this receptor is involved in the positive regulation of the
TCA cycle, steroidogenesis, bile acid metabolism, angiogenesis, the hexose mono-phosphate shunt,
mitochondrial amino acid transport, and that it also negatively regulates the rate limiting steps in the
glycolytic pathway. The linking of ERRa activity to mitochondrial function has reinvigorated interest in
this receptor sub-family as therapeutic targets in cancer, metabolic diseases and mitochondrial
dystrophies. Because of their structural similarity to the canonical estrogen receptors (ERa and ERp), it
has long been considered that the ERRs function as regulators of estrogen responsiveness. It now
appears, however, that activities unrelated to ER signaling are an equally important facet of ERR
biology. In this study a series of new technologies, which have been developed in our laboratory, will be
used (a) to define the specific role(s) of ERRa in liver biology and (b) to determine whether the
formation of different receptor-cofactor complexes are associated with different biological outcomes.
This work will provide an understanding of the physiological roles of this receptor subclass and will
establish a scientific framework upon which to build discovery programs aimed at developing
tissue/process-selective ERR modulators. These objectives will be realized upon completion of the
following specific aims: Aim 1: Definition of the physiological role(s) of ERRa in liver using customized
coactivators as protein ligands Aim 2: Identification of the molecular components of the ERRa signaling
pathways in liver Aim 3: Evaluation of the impact of cofactors on ERRa transcriptional activity Aim 4:
Examination of the biological consequence(s) of differential cof actor recruitment by ERRa: A test of the
coactivator hypothesis
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会议论文
Manipulating normal estrogen physiology as a therapeutic approach in cancer
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批准号:10561945
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项目类别:
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资助金额:$55.86万
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财政年份:2023
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依托单位:
Elucidation of the mechanisms by which cells recognize and respond to different levels of androgens
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批准号:10418461
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资助金额:$66.5万
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财政年份:2022
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负责人:Donald P McDonnell
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依托单位:
Development of Novel ERRalpha Antagonists as Breast Cancer Therapeutics
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批准号:10510732
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项目类别:
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资助金额:$25.49万
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财政年份:2022
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负责人:Donald P McDonnell
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依托单位:
Development of Novel ERRalpha Antagonists as Breast Cancer Therapeutics
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批准号:10684832
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项目类别:
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资助金额:$27.24万
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财政年份:2022
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依托单位:
The pharmacological actions of antiprogestins in uterine fibroids
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批准号:7504946
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项目类别:
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资助金额:$40.13万
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财政年份:2009
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负责人:Donald P McDonnell
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依托单位:
The pharmacological actions of antiprogestins in uterine fibroids
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批准号:7900905
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项目类别:
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资助金额:$41.54万
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财政年份:2009
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负责人:Donald P McDonnell
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依托单位:
Validation of the Estrogen Related Receptor as a therapeutic target in cancer
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批准号:7541738
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项目类别:
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资助金额:$33.15万
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财政年份:2007
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负责人:Donald P McDonnell
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依托单位:
Validation of the Estrogen Related Receptor as a therapeutic target in cancer
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批准号:7372733
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项目类别:
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资助金额:$33.15万
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财政年份:2007
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负责人:Donald P McDonnell
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依托单位:
Validation of the Estrogen Related Receptor as a therapeutic target in cancer
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批准号:8019621
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项目类别:
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资助金额:$32.49万
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财政年份:2007
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负责人:Donald P McDonnell
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依托单位:
Validation of the Estrogen Related Receptor as a therapeutic target in cancer
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批准号:8204677
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项目类别:
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资助金额:$32.49万
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财政年份:2007
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负责人:Donald P McDonnell
-
依托单位:
The role of ERRalpha/PGC-1 in disease pathogenesis
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批准号:8459862
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项目类别:
-
资助金额:$32.23万
-
财政年份:2006
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负责人:Donald P McDonnell
-
依托单位:
The role of ERRalpha/PGC-1 in disease pathogenesis
-
批准号:9195702
-
项目类别:
-
资助金额:$31.42万
-
财政年份:2006
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负责人:Donald P McDonnell
-
依托单位:
The role of ERRalpha/PGC-1 in disease pathogenesis
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批准号:8610906
-
项目类别:
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资助金额:$30.48万
-
财政年份:2006
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负责人:Donald P McDonnell
-
依托单位:
The role of ERRalpha/PGC-1 in disease pathogenesis
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批准号:8997471
-
项目类别:
-
资助金额:$31.42万
-
财政年份:2006
-
负责人:Donald P McDonnell
-
依托单位:
Conference on Tissue-Selective Nuclear Receptors
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批准号:6887878
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项目类别:
-
资助金额:$1.0万
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财政年份:2004
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负责人:Donald P McDonnell
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依托单位:
Nuclear Receptors: Steroid Sisters
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批准号:6748025
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项目类别:
-
资助金额:$0.6万
-
财政年份:2004
-
负责人:Donald P McDonnell
-
依托单位:
Molecular Determinants of Androgen Receptor Pharmacology
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批准号:7580170
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项目类别:
-
资助金额:$35.3万
-
财政年份:2003
-
负责人:Donald P McDonnell
-
依托单位:
Molecular Determinants of Androgen Receptor Pharmacology
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批准号:7074657
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项目类别:
-
资助金额:$33.84万
-
财政年份:2003
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负责人:Donald P McDonnell
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依托单位:
Molecular Determinants of Androgen Receptor Pharmacology
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批准号:7996009
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项目类别:
-
资助金额:$34.76万
-
财政年份:2003
-
负责人:Donald P McDonnell
-
依托单位:
Molecular Determinants of Androgen Receptor Pharmacology
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批准号:6896157
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项目类别:
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资助金额:$34.65万
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财政年份:2003
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负责人:Donald P McDonnell
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依托单位:
海外基金