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: 10615138
• 负责人: MARTIN S TAYLOR
• 金额: $ 17.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10615138
• 关键词: Address; Affect; Affinity; Aging; Allosteric Regulation; Apoptosis; Autophagocytosis; Award; Binding; Biochemical; Bioinformatics; Biological Assay; Biology; Biomedical Research; Catabolic Process; Catalysis; Chemicals; Clinical; Collaborations; Color; Complex; Cryoelectron Microscopy; Cytoskeleton; Data; Data Analyses; Development; Development Plans; Diabetes Mellitus; Disease; Ensure; Eukaryotic Cell; FRAP1 gene; Feedback; Fostering; Functional disorder; General Hospitals; Generations; Glucose Transporter; Goals; Growth; Growth Factor; Homeostasis; Hospital Departments; Human; Hypertension; Impairment; Institution; Insulin; Insulin Receptor; Insulin Resistance; International; Ion Channel; Kinetics; Knowledge; Learning; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Massachusetts; Measures; Mentors; Metabolic; Metabolic syndrome; Molecular Conformation; Monomeric GTP-Binding Proteins; Neoplasm Metastasis; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Oncogenic; PIK3CG gene; Pathologist; Pathology; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Physicians; Play; Positioning Attribute; Principal Investigator; Proliferating; Protein Engineering; Proteins; Proteomics; Reaction; Reagent; Regulation; Research; Research Personnel; Resolution; Role; Science; Scientist; Series; Signal Transduction; Solid Neoplasm; Structure; Substrate Interaction; System; Techniques; Testing; Therapeutic; Time; Training; Treatment Failure; Tuberous Sclerosis; Universities; Up-Regulation; Visualization; arm; blood glucose regulation; cancer type; career; career development; cell growth; cell motility; chemical conjugate; crosslink; density; design; experience; feeding; follow-up; gastrointestinal; glucose transport; human disease; inhibitor; insight; insulin sensitivity; insulin signaling; interest; mTOR inhibition; nanobodies; novel; pharmacologic; prevent; programs; protein complex; receptor sensitivity; research and development; rho; rho GTP-Binding Proteins; skill acquisition; small molecule; structural biology; success; therapy development; tool; transmission process

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