Role of the BCL-2 and caspase family in acinar apoptosis

唾液腺功能低下是影响美国数百万人生活质量的主要口腔健康问题。多种情况可导致唾液腺泡细胞分泌功能丧失，包括系统性疾病，如干燥综合征(一种自身免疫性疾病)、X射线照射、癌症化疗、心理因素、营养不良、药物引起的口干症和口腔癌。所有这些疾病状况或治疗方法都有可能改变正常唾液腺腺泡细胞的动态平衡，并加速唾液腺腺泡细胞进入细胞凋亡。如果我们想要完全理解唾液腺功能低下的具体机制，就需要对涎腺腺泡细胞凋亡所涉及的分子事件有一个基本的了解。这些信息对于开发新的治疗模式也是至关重要的，这些治疗模式有可能阻止或推迟这些不同疾病条件和治疗方法对正常腺泡细胞功能的毒性影响。这个项目的主要目标是在分子水平上研究和确定两个主要的细胞蛋白家族的确切功能，这两个蛋白家族在腺泡细胞凋亡的启动、信号转导和执行过程中发挥着核心作用。两个关键的调控蛋白家族是半胱氨酸天冬氨酸氨基转移酶和Bcl-2蛋白家族。我们将确定它们的表达水平、亚细胞分布、磷酸化水平和功能活性，在特定的凋亡刺激诱导的腺泡细胞凋亡的开始和持续时间内。这些研究将使用原代培养的大鼠腮腺和颌下腺泡细胞以及永生化的大鼠腮腺和颌下腺泡细胞系进行。这两个非常重要的蛋白质家族的鉴定和鉴定将为开发抑制腺泡细胞异常凋亡的新的治疗方法提供新的基本科学信息和见解，长期目标是改善数百万受影响的人的生活质量。

Salivary gland hypofunction is a major oral health problem that affects the quality of life for several million people in the USA. A variety of conditions can resulting in the loss of salivary acinar cell secretory function including systemic diseases such as Sjogren's Syndrome (an autoimmune disease), X-ray irradiation, cancer chemotherapy, psychological factors, malnutrition, pharmacological induced xerostomia and oral cancer. All of these disease conditions or treatments have the potential to alter normal salivary acinar cell homeostasis and to accelerate the entry of the salivary gland acinar cells into apoptosis. A fundamental understanding of the molecular events involved in salivary gland acinar apoptosis is required if we are to fully comprehend the specific mechanisms involved in salivary gland hypofunction. This information is also essential for the development of new treatment modalities that have the potential to block or delay the toxic effects of these various disease conditions and treatments on normal acinar cell function. The principle objective of this project is to investigate and determine at the molecular level the precise function of the two major cellular protein families that play a central role in the initiation signaling and execution of acinar cell apoptosis. The two critical regulatory protein families are the caspase and the Bcl-2 family of proteins. We will determine their level of expression, subcellular distribution, level of phosphorylation and their functional activity during t he onset and duration of acinar cell apoptosis elicited by specific apoptotic stimuli. These studies will be performed using primary cultures of rat parotid and sub-mandibular acinar cells and immortalized rat parotid and sub-mandibular acinar cell lines. The identification and characterization of these two critically important protein families will provide new basic scientific information and insights for the development of new therapeutic approaches to suppress aberrant acinar cell apoptosis, with the long term objective to improve the quality of life for millions of affected individuals.