Tousled kinase contributes to survival of salivary acinar cells against radiation

描述（由申请人提供）：积极的多模式治疗的引入帮助癌症幸存者比以前活得更长。许多癌症治疗都有有害的副作用，这些副作用也表现在口腔中。口腔并发症主要影响接受头颈癌、早期淋巴瘤放疗和骨髓移植前全身放疗的患者。放射治疗最常见和最痛苦的口腔症状是唾液减少。正常唾液腺的意外破坏会导致唾液分泌急剧下降，从而导致口干症或口干。口腔唾液减少会引起剧烈的灼痛，并使味觉、咀嚼、吞咽和说话等基本功能难以完成。它还会增加口腔感染、溃疡和快速蛀牙的风险。与口干症相关的发病率严重影响患者的生活质量、营养摄入和继续癌症治疗的能力。目前还没有治愈口干症的方法，现在的重点越来越放在预防上。引入新的放射治疗技术以避免唾液腺，在某种程度上帮助减轻了病情的严重程度，但并没有降低其发病率。口干症的治疗仍然是一个挑战。我们之前发现，正常细胞蛋白TLK1B （Tousled-like kinase 1B）水平的升高可以保护正常上皮细胞免受辐射诱导的细胞死亡。最近，我们证明了这种细胞保护作用在大鼠唾液细胞中是可重复的，并且细胞渗透性TLK1B可以减轻辐射诱导的大鼠唾液功能减退。为了确定最可行的临床转译方法，在本研究中，我们将研究1)使用HIV-TAT蛋白转导结构域的类似物改善TLK1B的渗透是否可以提高人类唾液腺泡细胞抗辐射的存活率，以及2)使用小分子激活内源性TLK1B是否可以防止辐射诱导的细胞死亡。我们的研究结果将进一步促进TLK1B蛋白治疗的临床前开发，并评估其激活剂在改善放射性口干症中的适用性。未来的研究可以着眼于确定蛋白质和药物联合治疗是否比单独治疗更有效。预防口干症不仅可以提高患者的治疗依从性，从而改善癌症预后，还可以提高患者的生活质量和作为癌症幸存者的自尊。

DESCRIPTION (provided by applicant): The introduction of aggressive multi-modality treatments have helped cancer survivors live longer than before. Many cancer treatments have deleterious side-effects, which also manifest in the oral cavity. Oral complications predominantly affect patients undergoing radiotherapy for head and neck cancers, early stage lymphomas, and full-body radiation before bone marrow transplantation. The most common and distressing oral symptom of radiotherapy is reduced saliva. The unintended destruction of normal salivary glands causes a dramatic drop in saliva production, leading to a condition referred to as xerostomia or dry mouth. Reduced saliva in the mouth causes intense burning pain and makes basic functions such as tasting, chewing, swallowing, and speaking difficult to perform. It also contributes to the risk of oral infections, ulcerations, and rapid tooth decay. The morbidity associated with xerostomia severely compromises a patient's quality of life, their nutritional intake and their ability to continue cancer treatment. There is no cure for xerostomia, and emphasis is now increasingly placed on prevention. Introduction of new radiotherapy techniques to spare the salivary glands has helped reduce, to some measure, the severity of the condition, but not its prevalence. The treatment of xerostomia continues to be a challenge. We had previously found that increased levels of a normal cellular protein, Tousled-like kinase 1B (TLK1B), can protect normal epithelial cells against radiation-induced cell death. Recently, we demonstrated that this cytoprotective effect is reproducible in rat salivary cells, and cell-permeable TLK1B can attenuate radiation-induced salivary hypofunction in rats. To determine the most viable approach for clinical translation, in the proposed study we will examine 1) whether improved penetration of TLK1B using analogs of HIV-TAT protein transduction domain can increase survival of human salivary acinar cells against radiation, and 2) whether activation of endogenous TLK1B using small molecules can protect against radiation-induced cell death. The results of our studies will further the preclinical development of TLK1B protein therapy and assess the applicability of its activators in ameliorating radiation- induced xerostomia. Future research can then be directed at determining whether a combination of protein and drug therapy will be more efficacious than either treatment alone. Prevention of xerostomia will not only improve a patient's treatment compliance and therefore, cancer prognosis, but also his quality of life and self-esteem as a cancer survivor.