PKCdelta and salivary gland radioprotection

摘要 在美国，每年有超过5万人被诊断出患有头颈癌，其中大多数人 将接受δ-Radiation(IR)治疗。这些患者中的许多人会经历衰弱的副作用，因为 IR对非肿瘤组织的损害，包括口腔粘膜、舌头和唾液腺。在……里面 特别是，唾液腺的破坏和由此导致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 从IR对唾液腺泡细胞的直接损伤和随后通过凋亡导致的细胞损失，而 永久性功能丧失可能是由于IR受损的腺体无法再生丢失的细胞所致 通过细胞凋亡。我们的长期目标是了解蛋白激酶C增量(PKCδ)是如何调节 研究唾液腺对IR的反应，以便制定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)抑制蛋白激酶Cδ的激活可抑制细胞凋亡，并提供 在头部和颈部IR小鼠模型中的强大辐射防护。然而，人们对此知之甚少。 蛋白激酶Cδ调控DNA损伤诱导细胞凋亡的机制 PKCδ提供辐射防护。在本提案的目标1和目标2中，我们将探讨抑制的假设 蛋白激酶Cδ的表达抑制细胞凋亡，并保护唾液免受IR损伤的初期或早期影响 腺体通过调节DNA损伤反应和增加DNA修复。除了压制 细胞凋亡，我们的初步数据表明，TKIs可以通过以下方式为唾液腺提供长期的辐射防护 促进唾液腺泡细胞体内再生。在目标3中，我们将探索TKI促进 唾液腺泡细胞的再生，并确定PKCδ的基因破坏是否提供长期的 通过类似的机制进行辐射防护。我们的研究将确定(S)背后的机制 通过抑制PKCδ和TKI对唾液腺的辐射防护，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，但 策略也可能对IR和IR患者的其他非肿瘤组织的保护有意义 化疗的可能性，从而对患者的生活质量和治疗效果产生重大影响 针对各种癌症患者的干预措施。

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.