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Targeting of mTOR Activity for Chemoprevention of Solar UV-induced Skin Cancer

靶向 mTOR 活性对太阳紫外线诱发的皮肤癌进行化学预防

基本信息

批准号：
8059919
负责人：
TIMOTHY BOWDEN
金额：
$ 17.64万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-12-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8059919
关键词：
5&apos -AMP-activated protein kinase Accounting Apoptotic Cell Proliferation Cessation of life Chemoprevention Chronic Clinic Clinical Trials Collaborations Decision Trees Development Drug Combinations Drug Delivery Systems Epidermis Growth Human Incidence Instruction Knockout Mice Lead Light Metformin Molecular Target Mus New Agents Pathway interactions Pharmaceutical Preparations Phase Phosphotransferases Population Preclinical Testing Process Program Research Project Grants Protein Microchips Punch Biopsy Resources Risk Role Signal Pathway Signal Transduction Sirolimus Skin Skin Cancer Skin Carcinogenesis Skin Carcinoma Sun Exposure Testing The Sun Tissue Microarray Transgenic Mice Translational Research UV induced cancer chemoprevention cancer diagnosis design human FRAP1 protein inhibitor/antagonist innovation irradiation keratinocyte mTOR Inhibitor mTOR Signaling Pathway mouse model pre-clinical prevent programs ultraviolet

项目摘要

PROJECT SUMMARY (See instructions): The hypothesis in this Project is that the Pl-3 kinase-Akt-mTOR and the AMP-activated protein kinase (i.e. AMPK)-mTOR signaling pathways are targets forthe development of topical chemoprevention agents to inhibit solar UV induced non-melanoma skin cancer by blocking the growth of or inducing the death of genetically altered and solar UV-initiated keratinocytes. Specific Aim 1: To use genetically modified mice to determine the functional roles of Akt-1 and mTOR in solar UV-induced mouse skin carcinogenesis. The experimental approach is to develop epidermis specific inducible, conditional knockout mice for Akt-1 and mTOR and use these mice to validate these molecular targets. These mice will be given to Project 2 to study cross talk between the Akt/mTOR and Fyn/RSK2 pathways. Specific Aim 2: To use genetically modified mice to determine the functional role of AMPK in solar UV-induced mouse skin carcinogenesis. The experimental approach Is to develop transgenic mice where constitutively active AMPK is specifically expressed in the epidermis and use these mice to validate the molecular target. Specific Aim 3: To utilize inhibitors of Akt and mTOR as well as AMPK activators independently or in combination to determine whether pharmacological modulation of these kinases inhibits solar UV-induced mTOR signaling, cell proliferation, anti-apoptotic signaling and skin carcinogenesis. The Akt inhibitor to be used is PHT-427. The mTOR Inhibitor is rapamycin and the AMPK activator is Metformin, In collaboration with Project 2 we will test combinations of drugs targeting the Akt/mTOR and Fyn/RSK2 signaling pathways Specific Aim 4: To crossvalidate Akt, mTOR and AMPK as molecular targets for the chemoprevention of solar UV-induced skin cancer between mouse and human skin using tissue microarrays and reverse phase protein microarrays. This aim will be carried out in collaboration with Project 3 and will involve solar light-irradiation of subjects and punch biopsies to be used for studying the activation of the target signaling pathways. Successful lead drugs or drug combinations that show chemoprevention activity in this preclinical Project will be tested in the clinic by Project 3. This highly interactive and clinically translational research program project focuses on the successful preclinical testing of targeted chemoprevention agents in innovative mouse models (Projects 1 and 2) followed by the design and implementation of clinical trials in at risk human populations (Project 3). Detailed descriptions of the decision-tree selection process as well as the interactions between Projects and Cores are found on the Resources Format Page.

项目概述（见说明）：