Tousled kinase contributes to survival of salivary acinar cells against radiation

混乱的激酶有助于唾液腺泡细胞抵抗辐射的存活

• 批准号: 8353588
• 负责人: Gulshan Sunavala-Dossabhoy
• 金额: $ 7.2万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-11 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353588
• 关键词: Acinar Cell; Adverse effects; Affect; Affinity; Animals; Attenuated; Biological Assay; Bone Marrow Transplantation; Burning Pain; Cancer Prognosis; Cancer Survivor; Candidiasis; Carcinogenesis Mechanism; Cell Death; Cell Proliferation; Cell Survival; Cells; Chimeric Proteins; Clinical; DNA Repair; DNA biosynthesis; Deglutition; Dental caries; Development; Distress; Dose; Drops; Effectiveness; Epithelial Cells; Flow Cytometry; Gland; HIV; Head and Neck Cancer; Hemagglutinin; Histidine; Homologous Gene; Human; Immunoblotting; Intake; Ion-Exchange Chromatography Procedure; Life; Lymphoma; Major salivary gland structure; Malignant Neoplasms; Mammals; Mastication; Measures; Mitochondria; Modality; Molecular; Molecular Chaperones; Morbidity - disease rate; Mucositis; Nutritional; Oral; Oral cavity; Oral health; Oxidoreductase; Patients; Penetration; Peptide Hydrolases; Peptides; Personal Satisfaction; Pharmacotherapy; Phosphotransferases; Plants; Predisposition; Prevalence; Prevention; Preventive; Production; Proteins; Quality of life; RNA Splicing; Radiation; Radiation therapy; Rattus; Recombinant Proteins; Risk; Safety; Saliva; Salivary; Salivary Glands; Severities; Staging; Symptoms; System; Taste Perception; Techniques; Testing; Toxic effect; Translating; Translations; Ulcer; Variant; Xerostomia; analog; cancer care; cancer therapy; cellular transduction; chromatin remodeling; compliance behavior; drug efficacy; fight against; improved; oral infection; overexpression; pre-clinical; research study; salivary acinar cell; salivary cell; self esteem; small molecule; synthetic protein; transduction efficiency

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. PUBLIC HEALTH RELEVANCE: Great strides in understanding the molecular mechanisms of carcinogenesis have helped the fight against cancer. The introduction of aggressive, multi-modality treatments has seen many cancer survivors live longer than before, but the accompanying deleterious side-effects of these treatments diminish the patient's quality of life. In this proposal we seek to further develop a preventive protein therapy and evaluate the efficacy of drugs that activate it in ameliorating the adverse effect of radiotherapy, salivary hypofunction.

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放疗、早期淋巴瘤以及骨髓移植前全身放疗的患者。放射治疗最常见且令人痛苦的口腔症状是唾液减少。正常唾液腺的意外破坏导致唾液分泌急剧下降，导致口干症。口腔中唾液减少会导致剧烈的灼痛，并使品尝、咀嚼、吞咽和说话等基本功能难以执行。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。口干症无法治愈，现在越来越重视预防。引入新的放射治疗技术来保护唾液腺，在某种程度上有助于降低病情的严重程度，但并不能降低其患病率。口干症的治疗仍然是一个挑战。 我们之前发现，正常细胞蛋白蓬乱样激酶 1B (TLK1B) 水平的增加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，并且细胞渗透性的 TLK1B 可以减轻辐射引起的大鼠唾液功能减退。为了确定临床转化的最可行方法，在拟议的研究中，我们将检查 1) 使用 HIV-TAT 蛋白转导结构域类似物提高 TLK1B 的渗透是否可以增加人类唾液腺泡细胞对辐射的存活率，以及 2) 是否激活使用小分子的内源性 TLK1B 可以防止辐射引起的细胞死亡。我们的研究结果将进一步推进 TLK1B 蛋白疗法的临床前开发，并评估其激活剂在改善辐射引起的口干症中的适用性。未来的研究可以确定蛋白质和药物的组合治疗是否比单独的治疗更有效。预防口干症不仅可以改善患者的治疗依从性，从而改善癌症预后，还可以改善患者的生活质量和作为癌症幸存者的自尊。 公共健康相关性：在了解致癌分子机制方面取得的巨大进步有助于对抗癌症。积极的多模式治疗的引入使许多癌症幸存者的寿命比以前更长，但这些治疗伴随的有害副作用降低了患者的生活质量。在这项提案中，我们寻求进一步开发一种预防性蛋白质疗法，并评估激活它的药物在改善放射治疗、唾液功能减退的副作用方面的功效。