Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy
癌症生物学和治疗中的内质网伴侣
基本信息
- 批准号:8934510
- 负责人:
- 金额:$ 133.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-01 至 2020-08-31
- 项目状态:已结题
- 来源:
- 关键词:ATPase DomainAchievementApplications GrantsAreaBasic ScienceBindingBiogenesisBiologicalBiological MarkersBiologyCancer BiologyCancer ModelCell physiologyCell surfaceCharacteristicsChemicalsClientClinicalCollaborationsComplexDataDevelopmentDiseaseDockingERBB2 geneEndoplasmic ReticulumFamilyGenerationsGoalsHeat-Shock Proteins 90HumanImmunologyInstitutesInstitutionIntegrinsInvestigationJointsKnock-in MouseKnockout MiceKnowledgeLaboratoriesLinkMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of ovaryMammary NeoplasmsMediatingMedicalMedical ResearchMembraneMemorial Sloan-Kettering Cancer CenterMitochondriaModelingMolecularMolecular ChaperonesMultiple MyelomaN-terminalNeoplasm MetastasisOncogenicPharmaceutical PreparationsPharmacologyPhenotypePost-Translational Protein ProcessingProcessProgram Research Project GrantsProteinsPublicationsPurinesRecording of previous eventsRecordsResearchResearch InstituteResourcesRoleSouth CarolinaStagingStructureSurfaceSystemTherapeuticTimeToll-like receptorsTransforming Growth Factor betaTranslationsTumor BiologyUniversitiesWorkbasecancer addictioncancer cellcancer therapycancer typeclinically relevantdesigndrug discoverygenetic approachinhibitor/antagonistinterestlipoprotein receptor-related protein 6malignant breast neoplasmmelanomamembermouse modelneglectnew therapeutic targetnovelparalogous genepre-clinical researchpreclinical studyprogramsprotein foldingpurinereceptorresponsescaffoldsmall moleculestructural biologysuccesstargeted treatmenttherapeutic targettooltumor progressiontumorigenesis
项目摘要
DESCRIPTION (provided by applicant): The overall goal of this PPG proposal is to advance fundamental understanding of grp94, a major oncogenic chaperone in the endoplasmic reticulum (ER), with the ultimate objective of developing rational grp94-based cancer therapeutics. Also known as gp96, endoplasmin, and Hsp90b1, grp94 is the recently evolved ERresident member of the HSP90 family. Its expression is upregulated by the unfolded protein response that is characteristic of cancer cells. Over-expression of grp94 in cancers uniformly correlates with advanced stage and poor survival. Four recent publications from this PPG group have further cemented the oncogenic roles of grp94. Despite its high relevance in cancer, the understanding of the function and mechanism of grp94 has lagged behind that of other molecular chaperones. This has now begun to change, with several key observations with regard to client repertoire, cellular function, disease implications, structural biology, and speciic inhibitors coming from the laboratories of this PPG team. This team has shown that grp94 is an essential master chaperone for Toll-like receptors (TLRs), integrins, Wnt co-receptor LRP6, HER2 and TGFβ- surface docking molecule GARP. The chaperone function of grp94 depends on its ATPase domain, which has been structurally resolved by the team and shown to be distinct from that of cytosolic Hsp90, enabling the successful development of several highly selective grp94 inhibitors. Two pressing tasks impede further advances in this field: 1) understanding the fundamental roles of grp94 in cancer biology; and 2) developing and validating effective grp94 inhibitors for development and clinical translation as grp94-based cancer therapeutics. This Program Project is designed to overcome both obstacles by uniting, in three Projects and two Cores, three leading laboratories in the field of grp94 research: biology (Li), structural biology (Gewirth) and drug discovery (Chiosis). This collaboration synergizes resources from three leading institutes -MUSC, Memorial Sloan-Kettering and Hauptman-Woodward - and builds on the Project Leaders' inherent shared interests, proven track records (57 joint publications) and complementary expertise. The specific goals of this PPG include: Project 1) Determine the role and significance of grp94 in controlling TGFβ biogenesis and TGFβ-mediated cancer progression via folding GARP and integrins; Project 2) Develop chemical tools that enable a spatio-temporal investigation of grp94-regulated cancer mechanisms in cancer phenotypes; Project 3) Elucidate the chaperone mechanism of grp94 as well as grp94 inhibitors from the structural point-of-view. The success of these projects will significantly advance understanding of how grp94 functions in cancer biology molecularly, why 'grp94-addiction' by cancer appears to span a wide spectrum of cancer types, how grp94 differs structurally and functionally from other HSP90 paralogs in binding to ATP and purine scaffold inhibitors, what are the ideal cancer types for grp94-targeted therapy, and whether a novel class of highly selective grp94 inhibitors can be used to probe the tumor biology and biological significance of grp94-client networks in cancer.
描述(由申请人提供):这项PPG提案的总体目标是促进对grp94的基本了解,grp94是内质网(ER)中的一种主要致癌伴侣,最终目标是开发合理的基于grp94的癌症疗法。Grp94也被称为gp96、内纤溶酶和Hsp90b1,是HSP90家族中最新进化的ER驻留成员。它的表达被癌细胞特有的未折叠蛋白反应上调。Grp94在癌症中的过度表达与晚期和低存活率一致相关。这个PPG小组最近发表的四篇论文进一步巩固了grp94的致癌作用。尽管grp94与癌症有很高的相关性,但对grp94的功能和机制的了解一直落后于其他分子伴侣。这种情况现在已经开始改变,这个PPG团队的实验室对客户曲目、细胞功能、疾病含义、结构生物学和特殊抑制剂的几个关键观察结果。该团队已经证明,GRP94是Toll样受体(TLRs)、整合素、Wnt共同受体LRP6、HER2和转化生长因子β-表面对接分子GARP的必需主伴侣。Grp94的伴侣功能依赖于其ATPase结构域,该结构域已被该团队从结构上解析,并被证明不同于胞质Hsp90,从而使几种高选择性grp94抑制剂的成功开发成为可能。两项紧迫的任务阻碍了这一领域的进一步发展:1)了解grp94在癌症生物学中的基本作用;2)开发和验证有效的grp94抑制剂,用于开发和临床翻译为基于grp94的癌症治疗药物。该计划项目旨在通过在三个项目和两个核心中联合grp94研究领域的三个领先实验室来克服这两个障碍:生物学(LI)、结构生物学(Gewirth)和药物发现(Chisis)。这一合作结合了三个领先机构--南加州大学、斯隆-凯特林纪念学院和豪普特曼-伍德沃德学院--的资源,并建立在项目领导人固有的共同兴趣、可靠的跟踪记录(57份联合出版物)和互补专业知识的基础上。该项目小组的具体目标包括:项目1)确定grp94在通过折叠GARP和整合素调控转化生长因子β生物发生和转化生长因子β介导的癌症进展中的作用和意义;项目2)开发能够在癌症表型中时空研究grp94调控的癌症机制的化学工具;项目3)从结构角度阐明grp94及其抑制剂的伴侣机制。这些项目的成功将大大提高人们对grp94在癌症生物学中的分子功能,为什么癌症对grp94上瘾的原因似乎跨越了广泛的癌症类型,grp94在结构和功能上与其他HSP90类似物在结合ATP和嘌呤支架抑制剂方面有何不同,哪些是grp94靶向治疗的理想癌症类型,以及是否可以使用一类新型的高选择性grp94抑制剂来探索grp94客户网络在癌症中的肿瘤生物学和生物学意义。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Zihai Li其他文献
Zihai Li的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Zihai Li', 18)}}的其他基金
Sexual Dimorphism in T Cell Exhaustion and Bladder Cancer
T 细胞耗竭和膀胱癌中的性别二态性
- 批准号:
10629078 - 财政年份:2023
- 资助金额:
$ 133.75万 - 项目类别:
Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy Supplement
靶向 GRP94-TGF-β 通路的癌症免疫治疗补充剂
- 批准号:
10818173 - 财政年份:2021
- 资助金额:
$ 133.75万 - 项目类别:
Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy
靶向 GRP94-TGF-β 通路的癌症免疫治疗
- 批准号:
10474548 - 财政年份:2021
- 资助金额:
$ 133.75万 - 项目类别:
Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy
靶向 GRP94-TGF-β 通路的癌症免疫治疗
- 批准号:
10689068 - 财政年份:2021
- 资助金额:
$ 133.75万 - 项目类别:
Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy
靶向 GRP94-TGF-β 通路的癌症免疫治疗
- 批准号:
10275810 - 财政年份:2021
- 资助金额:
$ 133.75万 - 项目类别:
Integration of inflammation and cancer by molecular chaperone
分子伴侣整合炎症和癌症
- 批准号:
10056559 - 财政年份:2017
- 资助金额:
$ 133.75万 - 项目类别:
Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy
癌症生物学和治疗中的内质网伴侣
- 批准号:
9321008 - 财政年份:2015
- 资助金额:
$ 133.75万 - 项目类别:
Project 1: Definition of grp94-GARP-TGFbeta Axis in Cancer Biology and Clinical Significance
项目1:grp94-GARP-TGFbeta轴在癌症生物学中的定义及其临床意义
- 批准号:
8934513 - 财政年份:2015
- 资助金额:
$ 133.75万 - 项目类别:
Novel mechanisms of UPR sensing and nonalcoholic fatty liver disease
UPR传感和非酒精性脂肪肝的新机制
- 批准号:
9026108 - 财政年份:2015
- 资助金额:
$ 133.75万 - 项目类别:
Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy
癌症生物学和治疗中的内质网伴侣
- 批准号:
9770790 - 财政年份:2015
- 资助金额:
$ 133.75万 - 项目类别:
相似海外基金
Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
- 批准号:
2335802 - 财政年份:2024
- 资助金额:
$ 133.75万 - 项目类别:
Standard Grant
Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
- 批准号:
2335801 - 财政年份:2024
- 资助金额:
$ 133.75万 - 项目类别:
Standard Grant
A Longitudinal Study of the Relationship between Participation in a Comprehensive Exercise Program and Academic Achievement
参加综合锻炼计划与学业成绩之间关系的纵向研究
- 批准号:
24K14615 - 财政年份:2024
- 资助金额:
$ 133.75万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Collaborative Research: Characterizing Best Practices of Instructors who Have Narrowed Performance Gaps in Undergraduate Student Achievement in Introductory STEM Courses
合作研究:缩小本科生 STEM 入门课程成绩差距的讲师的最佳实践
- 批准号:
2420369 - 财政年份:2024
- 资助金额:
$ 133.75万 - 项目类别:
Standard Grant
Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
- 批准号:
2335800 - 财政年份:2024
- 资助金额:
$ 133.75万 - 项目类别:
Standard Grant
WTG: Diffusion of Research on Supporting Mathematics Achievement for Youth with Disabilities through Twitter Translational Visual Abstracts
WTG:通过 Twitter 翻译视觉摘要传播支持残疾青少年数学成就的研究
- 批准号:
2244734 - 财政年份:2023
- 资助金额:
$ 133.75万 - 项目类别:
Standard Grant
The Impact of Emotional Experiences of Pride on Long-Term Goal Achievement Behaviors in Elite Athletes
骄傲的情感体验对优秀运动员长期目标实现行为的影响
- 批准号:
23K16740 - 财政年份:2023
- 资助金额:
$ 133.75万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Meta-Analysis of the Instructional-Relational Model of Student Engagement and Math Achievement: A Moderation and Mediation Approach
学生参与度和数学成绩的教学关系模型的元分析:一种调节和中介方法
- 批准号:
2300738 - 财政年份:2023
- 资助金额:
$ 133.75万 - 项目类别:
Standard Grant
Improving maths achievement in children with speech, language, and communication needs through 'collaborative vocabulary teaching'
通过“协作词汇教学”提高有言语、语言和交流需求的儿童的数学成绩
- 批准号:
2890475 - 财政年份:2023
- 资助金额:
$ 133.75万 - 项目类别:
Studentship
HSI Institutional Transformation Project: Retention and Achievement for Introductory STEM English Learners (RAISE)
HSI 机构转型项目:STEM 英语入门学习者的保留和成就 (RAISE)
- 批准号:
2225178 - 财政年份:2023
- 资助金额:
$ 133.75万 - 项目类别:
Continuing Grant