TRP Ca2+ Channels in the skin

描述（由申请人提供）：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性是EGFR信号的升高。事实上，抗EGFR策略（EGFR单克隆抗体和小分子酪氨酸激酶抑制剂；TKIs）是目前最常见的抗癌疗法之一。然而，大多数抗egfr药物会产生不良副作用，并且由于迅速产生耐药性，只能部分有效。我们寻求一种新的替代策略来治疗egfr依赖性癌。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之上，即TRPV3，一个在许多上皮组织中表达的Ca2+通道，包括皮肤，结肠和前列腺，是EGFR信号的关键调节剂。TRPV3与TGF-a/EGFR形成信号复合物；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TGF-a释放。在动物水平上，trpv3缺陷小鼠表现出与TGF-a/EGFR信号缺陷小鼠相似的毛发/皮肤表型。因此，TRPV3可能成为皮肤和其他上皮癌的新治疗靶点。虽然离子通道不是癌症治疗的已知靶点，但最近报道TRPV3是结直肠癌的高危基因。此外，小分子TRPV3抑制剂正在临床试验中，用于减轻炎症介质引起的疼痛，其中许多炎症介质也是有效的肿瘤促进剂。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。通过皮肤癌变动物模型，我们将研究在上皮恶性肿瘤过程中TRPV3的表达和通道功能是否上调，以及TRPV3基因和药理学失活是否可能延缓上皮肿瘤的促进/进展。我们的第一个目的是研究TRPV3在角质细胞转化和皮肤肿瘤发生过程中的表达/功能。我们的第二个目标是使用转基因TRPV3表达的小鼠研究TRPV3在皮肤肿瘤发展中的作用。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。总的来说，TRPV3和EGFR信号在正常表皮上的密切相互作用以及EGFR信号在癌症中的良好作用表明TRPV3在上皮肿瘤发生中的作用。这项研究的目的是为开发新的皮肤和其他上皮性癌症的治疗策略奠定必要的基础。

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. PUBLIC HEALTH RELEVANCE: The majority of human cancers arise in the epithelial tissues of organs such as breast, colon, prostate, and skin. The outcome of our proposed research should provide clinical insights into therapeutic approaches for skin and other epithelial cancers.