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中，如皮肤和结肠。 上皮细胞的不受控制的增殖通常由生长因子和细胞因子的异常信号传导引起。在许多上皮肿瘤中的共同点是EGFR信号传导的升高。 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; TKI）是目前最常见的抗癌疗法之一。然而，大多数抗EGFR药物会引起不良副作用，并且由于快速发展的药物耐受性而仅部分有效。我们寻求一种替代和新的策略来治疗EGFR依赖性癌症。我们的建议旨在建立在我们最近取得的，意想不到的，发现TRPV 3，在许多上皮组织，包括皮肤，结肠和前列腺中表达的Ca 2+通道，是EGFR信号传导的关键调节因子。TRPV 3与TGF-α/EGFR形成信号传导复合物; EGFR的活化导致TRPV 3通道活性增加，这反过来刺激由ADAM家族脱落酶介导的TGF-α释放。在动物水平，TRPV 3缺陷型小鼠表现出与TGF-α/EGFR信号传导缺陷型小鼠相似的毛发/皮肤表型。因此，TRPV 3可能是皮肤和其他上皮癌的新治疗靶点。虽然离子通道不是已知的癌症治疗靶点，但最近报道TRPV 3是结直肠癌的高危基因。此外，小分子TRPV 3抑制剂正在临床试验中用于减轻由炎症介质诱导的疼痛，其中许多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TRPV 3通道上调是加速皮肤肿瘤发生的适应不良。使用皮肤癌发生的动物模型，我们将研究TRPV 3表达和通道功能是否在上皮恶性肿瘤过程中上调，以及TRPV 3的遗传和药理学失活是否可能延迟上皮肿瘤的促进/进展。我们的第一个目的是研究TRPV 3在角质形成细胞转化和皮肤肿瘤发生过程中的表达/功能。我们的第二个目的是使用转基因表达TRPV 3的小鼠研究TRPV 3在皮肤肿瘤发展中的作用。我们的第三个目标是使用TRPV 3特异性小分子抑制剂研究TRPV 3在皮肤肿瘤发展中的作用。总的来说，TRPV 3和EGFR信号在正常表皮上的密切相互作用以及EGFR信号在癌症中的充分证实的作用表明TRPV 3在上皮肿瘤发生中的作用。这项拟议研究的目标是为开发皮肤癌和其他上皮癌的新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.