Elucidating structural, mechanistic, and allosteric determinants of mTOR Complex 2 (mTORC2) signaling.
阐明 mTOR 复合物 2 (mTORC2) 信号传导的结构、机制和变构决定因素。
基本信息
- 批准号:10615138
- 负责人:
- 金额:$ 17.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-15 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAffinityAgingAllosteric RegulationApoptosisAutophagocytosisAwardBindingBiochemicalBioinformaticsBiological AssayBiologyBiomedical ResearchCatabolic ProcessCatalysisChemicalsClinicalCollaborationsColorComplexCryoelectron MicroscopyCytoskeletonDataData AnalysesDevelopmentDevelopment PlansDiabetes MellitusDiseaseEnsureEukaryotic CellFRAP1 geneFeedbackFosteringFunctional disorderGeneral HospitalsGenerationsGlucose TransporterGoalsGrowthGrowth FactorHomeostasisHospital DepartmentsHumanHypertensionImpairmentInstitutionInsulinInsulin ReceptorInsulin ResistanceInternationalIon ChannelKineticsKnowledgeLearningMalignant NeoplasmsMapsMass Spectrum AnalysisMassachusettsMeasuresMentorsMetabolicMetabolic syndromeMolecular ConformationMonomeric GTP-Binding ProteinsNeoplasm MetastasisNon-Insulin-Dependent Diabetes MellitusNutrientOncogenicPIK3CG genePathologistPathologyPathway interactionsPharmaceutical PreparationsPhosphorylationPhosphotransferasesPhysiciansPlayPositioning AttributePrincipal InvestigatorProliferatingProtein EngineeringProteinsProteomicsReactionReagentRegulationResearchResearch PersonnelResolutionRoleScienceScientistSeriesSignal TransductionSolid NeoplasmStructureSubstrate InteractionSystemTechniquesTestingTherapeuticTimeTrainingTreatment FailureTuberous SclerosisUniversitiesUp-RegulationVisualizationarmblood glucose regulationcancer typecareercareer developmentcell growthcell motilitychemical conjugatecrosslinkdensitydesignexperiencefeedingfollow-upgastrointestinalglucose transporthuman diseaseinhibitorinsightinsulin sensitivityinsulin signalinginterestmTOR inhibitionnanobodiesnovelpharmacologicpreventprogramsprotein complexreceptor sensitivityresearch and developmentrhorho GTP-Binding Proteinsskill acquisitionsmall moleculestructural biologysuccesstherapy developmenttooltransmission process
项目摘要
Taylor, Martin | K08 (PA-20-203) | PROJECT SUMMARY / ABSTRACT
This proposal details a five-year training plan for the development of a research program focused on elucidating
structural, mechanistic, and allosteric determinants of mTOR Complex 2 (mTORC2) signaling. Phosphorylation
of the signaling kinase Akt on Ser473 by mTOR Complex 2 (mTORC2) is a critical regulated intracellular step in
insulin and other growth factor signaling. Ser473 phosphorylation activates Akt and is required for Akt’s
downstream metabolic effects, such as glucose transporter upregulation, which are dysregulated in diabetes,
and proliferation and growth, which are dysregulated in cancer. Therapeutic modulation of mTORC2 is therefore
of interest in the treatment of both diabetes and cancer but is not yet possible due to similarities between
mTORC2 and the better-understood effector complex mTORC1, which shares key components mTOR and
mLST8. mTORC2 also activates other substrates with less-defined roles in ion channel homeostasis, apoptosis,
cell motility, metastasis, and insulin receptor sensitivity, and its activity is modulated by a series of allosteric
interacting proteins including the small GTPases Rho and Ras. However, despite the central role of mTORC2-
Akt signaling, we have little information about how this critical reaction is catalyzed by mTORC2, how mTORC2
recognizes Akt and other substrates, or how these interactions are modulated allosterically. This project therefore
seeks to develop a detailed structural and mechanistic understanding of mTORC2 recognition of its substrates,
using novel enzymologic assays, protein engineering, and a combination of biochemical, chemical, proteomic,
and structural biology approaches that will also develop proof-of-concept inhibitors and potentially activators of
mTORC2.
My proposed studies will:
(i) provide detailed structural and mechanistic insight into mTOR Complex 2 kinase signaling
(ii) develop tools, reagents, and techniques applicable to other systems of interest, including mTORC1
(iii) provide ample opportunities for mechanistic and translational follow-up for my transition to independence.
I am a practicing gastrointestinal pathologist and physician scientist seeking K08 support for mentored research
under the guidance of Dr. David Sabatini and Dr. Philip Cole. This mentored period of 80% research and career
development and 20% clinical time will ensure I acquire the skills required to become a successful independent
principal investigator. Drs. Sabatini and Cole are internationally recognized mentors, together training ~40
successful independent investigators. My training will occur at two world-class institutions, the Whitehead
Institute for Biomedical Research, and Massachusetts General Hospital Department of Pathology. Both are rich
with opportunities for young scientists to train, pursue highly impactful science, and foster long-lasting
collaborations. I will also be guided by a committee of researchers that are all leaders in their fields: Dr. Joseph
Davis (MIT, structural biology of large protein complexes and cryoEM data analysis) and Dr. Yi Shi (University
of Pittsburgh, crosslinking mass spectrometry as applied to large protein complexes and nanobody generation).
The support of this K08 award will allow me to focus on maturing my research and strengthening my career
development during this critical last stage of mentored training. At the conclusion of my award period, I will be
optimally positioned for achieving success as an independent physician scientist.
Taylor, Martin | K08 (PA-20-203) |项目综述/摘要
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 }}
MARTIN S TAYLOR其他文献
MARTIN S TAYLOR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('MARTIN S TAYLOR', 18)}}的其他基金
Elucidating structural, mechanistic, and allosteric determinants of mTOR Complex 2 (mTORC2) signaling.
阐明 mTOR 复合物 2 (mTORC2) 信号传导的结构、机制和变构决定因素。
- 批准号:
10284076 - 财政年份:2021
- 资助金额:
$ 17.11万 - 项目类别:
Elucidating structural, mechanistic, and allosteric determinants of mTOR Complex 2 (mTORC2) signaling.
阐明 mTOR 复合物 2 (mTORC2) 信号传导的结构、机制和变构决定因素。
- 批准号:
10450814 - 财政年份:2021
- 资助金额:
$ 17.11万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 17.11万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 17.11万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 17.11万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 17.11万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 17.11万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 17.11万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 17.11万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 17.11万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 17.11万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 17.11万 - 项目类别:
Grant-in-Aid for Early-Career Scientists