PKCdelta and salivary gland radioprotection

摘要 在美国，每年有超过50，000人被诊断患有头颈癌（HNC），其中大多数人 将接受δ-照射（IR）治疗。这些患者中的许多人将经历使人衰弱的副作用， 非肿瘤组织，包括口腔粘膜、舌和唾液腺的IR损伤的结果。在 特别是，唾液腺的破坏和由此产生的功能减退是永久性的，并与 慢性口腔感染、龋齿和严重不适。唾液腺功能的早期丧失被认为是 由于IR对唾液腺泡细胞的直接损伤和随后的细胞凋亡引起的细胞损失， 永久性功能丧失可能是由于IR损伤的腺体不能再生失去的细胞 通过凋亡。我们的长期目标是了解蛋白激酶C δ（PKCδ）如何调节细胞内的蛋白质， 唾液腺对IR的反应，从而开发更好的辐射防护策略。我们的研究表明 使用酪氨酸激酶抑制剂（TKI）抑制PKCδ活化可抑制细胞凋亡， 在小鼠头颈部IR模型中， PKCδ调节DNA损伤诱导的细胞凋亡的机制，以及相反， PKCδ提供辐射防护。在本提案的目标1和2中，我们将探讨抑制 PKCδ抑制细胞凋亡，并保护唾液抵抗IR损伤的初始或“早期”效应。 腺体通过调节DNA损伤反应和增加DNA修复。除了抑制 细胞凋亡，我们的初步数据表明，TKI可以提供长期的放射保护唾液腺， 促进体内唾液腺泡细胞再生。在目标3中，我们将探讨TKI促进 唾液腺泡细胞的再生，并确定PKCδ的遗传破坏是否提供长期的 辐射防护类似的机制。我们的研究将确定潜在的机制 通过抑制PKCδ和TKI对唾液腺的辐射保护作用，并可能导致新的 口腔组织辐射防护的“合理”策略。虽然我们的重点是唾液腺， 这些策略也可能对保护经历IR的患者的其他非肿瘤组织有意义， 化疗的可能性，从而对生活质量和治疗效果产生重大影响。 对各种癌症患者进行干预。

ABSTRACT Over 50,000 people a year are diagnosed with head and neck cancer (HNC) in the US, the majority of whom will be treated with δ-irradiation (IR) therapy. Many of these patients will experience debilitating side effects as a consequence of IR damage to non-tumor tissues, including the oral mucosa, tongue and salivary glands. In particular, destruction of the salivary glands, and resultant hypofunction, is permanent and associated with chronic oral infections, caries, and severe discomfort. Early loss of salivary gland function is thought to result from direct damage to salivary acinar cells by IR and the subsequent loss of cells through apoptosis, while permanent loss of function likely results from the inability of the IR damaged gland to regenerate cells lost through apoptosis. Our long-term goal is to understand how protein kinase C delta (PKCδ) regulates the response of the salivary gland to IR, so as to develop better strategies for radioprotection. Our studies show that inhibition of PKCδ activation using tyrosine kinase inhibitors (TKIs) suppresses apoptosis and provides robust radioprotection in mouse models of head and neck IR. However, very little is known about the mechanisms by which PKCδ regulates DNA damage induced apoptosis, and conversely, how inhibition of PKCδ provides radioprotection. In Aims 1 and 2 of this proposal, we will explore the hypothesis that inhibition of PKCδ suppresses apoptosis and protects against the initial, or “early” effects of IR damage to the salivary gland through regulation of the DNA damage response and increased DNA repair. In addition to suppressing apoptosis, our preliminary data suggests that TKIs can provide long term radioprotection of salivary gland by promoting salivary acinar cell regeneration in vivo. In Aim 3 we will explore the hypothesis that TKIs promote regeneration of salivary acinar cells, and establish whether genetic disruption of PKCδ provides long term radioprotection though a similar mechanism. Our studies will define the mechanism(s) underlying radioprotection of the salivary gland by inhibition of PKCδ and TKIs, and may lead to the identification of new “rational” strategies for radioprotection for oral tissues. Although our focus is on the salivary gland, such strategies may also have implications for protection of other non-tumor tissues in patients undergoing IR and possibility chemotherapy, thus having a significant impact on the quality of life and efficacy of therapeutic interventions for a wide variety of cancer patients.