PKCdelta and chromatin remodeling

摘要 在美国，每年有超过50，000人被诊断出患有头颈癌（HNC），其中大多数人将 用δ-辐射（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损伤的后果。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。我们的长期目标是了解蛋白激酶C PKC δ调节唾液腺对胰岛素抵抗的反应，从而为胰岛素抵抗的治疗提供更好的策略。 辐射防护我们以前的研究表明，使用酪氨酸激酶抑制剂抑制PKCδ活化， （TKI）抑制细胞凋亡，并在头颈部IR小鼠模型中提供稳健的放射保护。 然而，对于PKCδ调节DNA损伤诱导的细胞凋亡的机制知之甚少， 相反，抑制PKCδ如何提供辐射防护。我们的研究在目标2的母资助地址 PKCδ减少凋亡/增加存活的假设（即，提供唾液腺 通过增加DNA修复的辐射防护。根据我们对这一目标的初步数据，我们要求 合作补充，以探索以前未知的作用，PKCδ在染色质重塑。我们提出 与我们机构的染色质生物学专家布莱克博士合作，询问DNA修复的调控是否 通过PKCδ介导的染色质结构的变化，并确定染色质调节酶 DNA修复和染色质结构中PKCδ依赖性变化所必需的。我们建议与 博士黑色是必不可少的，因为我的实验室没有这种专业知识。这些研究可能直接将PKCδ- 调节染色质调节酶具有辐射防护作用。未来的研究将确定， 染色质重塑可用于体内唾液腺的辐射防护。

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. 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 previous 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. Our studies in Aim 2 of the parent grant address the hypothesis that PKCδ decreases apoptosis/increases survival (i.e., provides salivary gland radioprotection) by increasing DNA repair. Based on our preliminary data toward this Aim, we are requesting a collaborative supplement to explore a previously unknown role for PKCδ in chromatin remodeling. We propose to collaborate with Dr. Black, an expert in chromatin biology at our institution, to ask if regulation of DNA repair by PKCδ is mediated through changes in chromatin structure, and identify chromatin regulatory enzymes required for PKCδ-dependent changes in DNA repair and chromatin structure. Our proposed collaboration with Dr. Black is essential as this expertise is not available in my laboratory. These studies may directly link a PKCδ- regulated chromatin regulating enzyme with radioprotection. Future studies will determine if regulators of chromatin remodeling can be used for radioprotection of the salivary gland in vivo.