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：
8607942
负责人：
Theresa Diane Carr
金额：
$ 4.77万
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 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607942
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 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 public health relevance research study response role model skin cancer prevention 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. PUBLIC HEALTH RELEVANCE: Nonmelanoma skin cancer (NMSC) is the most common cancer worldwide and the increasing rates of NMSC are associated with increased sun exposure. This research aims to better understand the function of the protein mTOR within skin cells. mTOR is activated by sun exposure, and we believe mTOR contributes to the development of skin cancer. Our research will investigate mTOR as a possible target for the prevention of skin cancer.

描述（由申请人提供）：非黑色素瘤皮肤癌 (NMSC) 是全球最常见的癌症，仅在美国每年诊断出的新病例就超过 100 万例。人类皮肤经常暴露在紫外线下，导致 DNA 损伤，从而导致皮肤老化和皮肤癌的发生。细胞凋亡对于消除含有致癌突变的受损皮肤细胞至关重要。然而，角质形成细胞已经进化出针对细胞凋亡的保护机制。这些机制不仅可以维持细胞稳态和表皮完整性，还可以作为皮肤细胞发展为 NMSC 的途径。哺乳动物雷帕霉素靶点 (mTOR) 信号传导在表皮中被 UVB 激活，并且已知可激活细胞增殖和促生存信号级联。研究表明 mTOR 可能是 NMSC 的一个有用的治疗靶点。然而，需要更好地了解 mTOR 在表皮细胞中对 UVB 反应的作用，这可能有助于确定预防 NMSC 的新靶点。我们假设选择性抑制 mTOR 将增加角质形成细胞对 UVB 诱导的细胞凋亡的敏感性，并阻止启动细胞的克隆扩张，从而抑制皮肤肿瘤的发生。拟议的实验将使用药物抑制剂雷帕霉素和基因消融技术来阻断角质形成细胞中的 mTOR 信号传导，并将检查对 UVB 暴露的体外和体内反应。如果我们的假设在该项目完成时得到证实，我们将把 mTOR 确立为表皮稳态的关键调节剂和 NMSC 中有吸引力的化疗预防靶点。公众健康相关性：非黑色素瘤皮肤癌 (NMSC) 是世界范围内最常见的癌症，NMSC 发病率的增加与阳光照射的增加有关。这项研究旨在更好地了解皮肤细胞内蛋白质 mTOR 的功能。 mTOR 会被阳光照射激活，我们相信 mTOR 会导致皮肤癌的发生。我们的研究将调查 mTOR 作为预防皮肤癌的可能目标。