mTOR signaling in keratinocyte UVB response

角质形成细胞 UVB 反应中的 mTOR 信号传导

基本信息

批准号：
8811424
负责人：
Theresa Diane Carr
金额：
$ 3.07万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8811424
关键词：
Ablation Accounting Actinic keratosis Address Apoptosis Apoptotic Bromodeoxyuridine CD34 gene Cell Differentiation process Cell Proliferation Cell Survival Cells Characteristics Clonal Expansion Complex DNA Damage Development Diagnosis Epidermis Exposure to FVB Mouse Figs - dietary Genetic Goals Growth Hair follicle structure Health Homeostasis Human Immunosuppressive Agents In Vitro Incidence Integrins Kidney Transplantation Label Lead Lesion Malignant Neoplasms Mediating Mediator of activation protein Molecular Mus Mutation Oncogenic Pathway interactions Patients Phenotype Play Property Relative (related person)Research Resistance Role Signal Transduction Signal Transduction Pathway Sirolimus Skin Skin Aging Skin Cancer Skin Carcinogenesis Skin Carcinoma Squamous cell carcinoma Stem cells Sun Exposure Techniques Topical application Transplant Recipients UVB carcinogenesis UVB induced Ultraviolet B Radiation Ultraviolet Rays cancer diagnosis cancer prevention carcinogenesis cell growth human FRAP1 protein in vivo inhibitor/antagonist keratinocyte mTOR Inhibitor mTOR protein mouse model new therapeutic target prevent protein complex protein function research study response skin cancer prevention stem cell differentiation theories therapeutic target tumor initiation tumorigenesis ultraviolet irradiation

项目摘要

DESCRIPTION (provided by applicant): Nonmelanoma skin cancer (NMSC) is the most prevalent cancer worldwide, with over 1 million new cases diagnosed each year in the US alone. Human skin is constantly exposed to UV light causing DNA damage that contributes to skin aging and the development of skin cancer. Apoptosis is essential to eliminate damaged skin cells harboring oncogenic mutations; however, keratinocytes have evolved protective mechanisms against apoptosis. These mechanisms act to preserve cellular homeostasis and epidermal integrity but can also act as a pathway for skin cells to progress to NMSC. Mammalian target of rapamycin (mTOR) signaling is activated in the epidermis by UVB, and is known to activate cell proliferation and pro- survival signaling cascades. Studies suggest that mTOR might be a useful therapeutic target in NMSC. However, a better understanding of mTOR's role in epidermal cells in response to UVB is needed and may lead to the identification of new targets to prevent NMSC. We hypothesize that selectively inhibiting mTOR will increase the sensitivity of keratinocytes to UVB-induced apoptosis and prevent the clonal expansion of initiated cells, thus inhibiting skin tumorigenesis. The proposed experiments will use the pharmacological inhibitor rapamycin and a genetic ablation technique to block mTOR signaling in keratinocytes and will examine the in vitro and in vivo responses to UVB exposure. If our hypothesis is substantiated at the completion of this project, we will establish mTOR as a critical regulator of epidermal homeostasis and an attractive chemo preventative target in NMSC.

描述（由申请人提供）：非黑色素瘤皮肤癌（NMSC）是全球最普遍的癌症，仅在美国，每年就会诊断出超过100万例新病例。人皮肤不断暴露于紫外线，导致DNA损伤，导致皮肤衰老和皮肤癌的发展。凋亡对于消除具有致癌突变的受损的皮肤细胞至关重要。然而，角质形成细胞已经发展出抗凋亡的保护机制。这些机制可以保留细胞稳态和表皮完整性，但也可以充当皮肤细胞发展到NMSC的途径。 UVB在表皮中激活了雷帕霉素（MTOR）信号的哺乳动物靶标，并且已知会激活细胞增殖和促生存信号传导级联。研究表明，MTOR可能是NMSC中有用的治疗靶标。但是，需要更好地理解MTOR在对表皮细胞中的作用，以响应UVB，并可能导致鉴定新目标以防止NMSC。我们假设有选择地抑制MTOR将增加角质形成细胞对UVB诱导的细胞凋亡的敏感性，并防止启动细胞的克隆膨胀，从而抑制皮肤肿瘤发生。提出的实验将使用药理学抑制剂雷帕霉素和遗传消融技术来阻断角质形成细胞中的MTOR信号传导，并将检查体外和体内对UVB暴露的反应。如果我们的假设在该项目的完成后得到证实，我们将建立MTOR作为表皮稳态的关键调节剂，并且在NMSC中成为有吸引力的化学预防靶标。