TRP Ca2+ Channels in the Skin

皮肤中的 TRP Ca2 通道

• 批准号: 8529459
• 负责人: Haoxing Xu
• 金额: $ 32.29万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529459
• 关键词: Adverse effects; Animal Model; Animals; Biochemical; Biological Assay; Breast; Carcinoma; Cells; Clinical; Clinical Trials; Colon; Colorectal Cancer; Complex; Cutaneous; Development; Drug Tolerance; Electrophysiology (science); Epidermal Growth Factor Receptor; Epidermis; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Exhibits; Family; Feedback; Genes; Genetic; Goals; Growth; Growth Factor; Hair; Human; Image; In Vitro; Inbred HRS Mice; Inflammation Mediators; Ion Channel; Malignant Neoplasms; Mediating; Molecular; Monoclonal Antibodies; Mus; Mutation; Nude Mice; Oncogenes; Oncogenic; Organ; Outcome; Pain; Paper; Papilloma; Phenotype; Predisposition; Prevention; Prostate; Protocols documentation; Publishing; Reporting; Research; Resistance; Role; Signal Transduction; Skin; Skin Carcinogenesis; Skin Neoplasms; Skin Papilloma; Squamous cell carcinoma; Staging; Testing; Therapeutic; Tissues; Transgenic Mice; Tumor Promotion; Tyrosine Kinase Inhibitor; Ultraviolet B Radiation; Up-Regulation; base; cancer therapy; carcinogenesis; chemical carcinogenesis; cytokine; gain of function; high risk; in vivo Model; inhibitor/antagonist; insight; irradiation; keratinocyte; killings; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutics; overexpression; ras Oncogene; small molecule; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The majority of human cancers arise in the epithelial tissues of organs such as skin and colon. Uncontrolled proliferation of epithelial cells is often caused by aberrant signaling of growth factors and cytokines. A commonality among many epithelial tumors is an elevation of EGFR signaling. In fact, anti-EGFR strategies (EGFR monoclonal antibodies and small molecule tyrosine-kinase inhibitors; TKIs) are currently among the most common anti-cancer therapies. However, most anti-EGFR agents cause adverse side effects and are only partially effective due to quickly developed drug tolerance. We seek an alternative and novel strategy to treat EGFR-dependent carcinomas. Our proposal seeks to build on our recently made, and unexpected, discovery that TRPV3, a Ca2+ channel expressed in many epithelial tissues, including skin, colon, and prostate, is a key regulator of EGFR signaling. TRPV3 forms a signaling complex with TGF-a/EGFR; activation of EGFR leads to increased TRPV3 channel activity, which in turn stimulates TGF-a release mediated by ADAM-family sheddase. At the animal level, TRPV3-deficient mice exhibit similar hair/skin phenotypes as mice with defective TGF-a/EGFR signaling. Thus, TRPV3 could be a novel therapeutic target for skin and other epithelial cancers. Although ion channels are not known targets for cancer treatment, TRPV3 is recently reported to be a high-risk gene in colorectal cancer. Moreover, small molecule TRPV3 inhibitors are in clinical trials for reducing pain induced by inflammatory mediators, many of which are also potent tumor-promoting agents. Therefore, we specifically hypothesize that TRPV3 channel up-regulation in keratinocytes is a maladaption that accelerates skin tumorigenesis. Using animal models of skin carcinogenesis, we will investigate whether TRPV3 expression and channel function are up-regulated during epithelial malignancy, and whether genetic and pharmacological inactivation of TRPV3 may delay promotion/progression of epithelial tumors. Our first aim is to investigate TRPV3 expression/function during keratinocyte transformation and skin tumorigenesis. Our second aim is to study the roles of TRPV3 in the development of skin tumors using mice with genetically modified expression of TRPV3. Our third aim is to investigate the roles of TRPV3 in the development of skin tumors using TRPV3-specific small molecule inhibitors. Overall, the close interaction of TRPV3 and EGFR signaling on normal epidermis and the well-demonstrated role of EGFR signaling in cancer suggest a role of TRPV3 in epithelial tumorigenesis. The goal of this proposed research is to lay the groundwork necessary to develop new therapeutic strategies for skin and other epithelial cancers.

描述(申请人提供)：大多数人类癌症发生在器官的上皮组织，如皮肤和结肠。上皮细胞的不受控制的增殖通常是由生长因子和细胞因子的异常信号引起的。许多上皮性肿瘤的一个共同点是EGFR信号的升高。事实上，抗EGFR策略(EGFR单抗和小分子酪氨酸激酶抑制剂；TKI)目前是最常见的抗癌疗法之一。然而，大多数抗EGFR药物都会产生不良反应，并且由于迅速形成药物耐受性而只有部分有效。我们寻求一种替代和新的策略来治疗EGFR依赖的癌症。我们的建议旨在建立在我们最近取得的和意想不到的发现的基础上，TRPV3是一种在包括皮肤、结肠和前列腺在内的许多上皮组织中表达的钙通道，是EGFR信号的关键调节因子。TRPV3与转化生长因子-α/表皮生长因子受体形成信号复合体；EGFR的激活导致TRPV3通道活性增加，进而刺激由ADAM家族脱落酶介导的转化生长因子-α的释放。在动物水平上，TRPV3缺陷小鼠的毛发/皮肤表型与转化生长因子-α/表皮生长因子受体信号缺陷小鼠相似。因此，TRPV3可能成为治疗皮肤癌和其他上皮性癌的新靶点。尽管离子通道不是已知的癌症治疗靶点，但最近有报道称TRPV3是结直肠癌的高危基因。此外，小分子TRPV3抑制剂正在进行临床试验，以减轻炎症介质引起的疼痛，其中许多也是有效的促癌药物。因此，我们特别假设角质形成细胞中的TRPV3通道上调是一种加速皮肤肿瘤发生的不适应。我们将利用皮肤癌的动物模型，研究TRPV3的表达和通道功能在上皮性肿瘤发生过程中是否上调，以及TRPV3的遗传和药物失活是否可能延缓上皮性肿瘤的发生和发展。我们的第一个目标是研究TRPV3在角质形成细胞转化和皮肤肿瘤发生过程中的表达和功能。我们的第二个目标是通过转基因表达TRPV3的小鼠来研究TRPV3在皮肤肿瘤发生中的作用。我们的第三个目标是利用TRPV3特异性小分子抑制剂研究TRPV3在皮肤肿瘤发展中的作用。总体而言，TRPV3和EGFR信号在正常表皮上的密切相互作用以及EGFR信号在癌症中的作用已得到充分证实，这表明TRPV3在上皮性肿瘤的发生中发挥了作用。这项拟议研究的目标是为开发新的皮肤癌和其他上皮性癌症的治疗策略奠定必要的基础。