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

唾液腺功能减退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，包括全身疾病，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、药物引起的口干和口腔癌。所有这些疾病或治疗都有可能改变正常的唾液腺腺泡细胞稳态，加速唾液腺腺泡细胞进入凋亡。如果我们要充分理解唾液腺功能减退的具体机制，就需要对唾液腺腺泡凋亡的分子事件有一个基本的了解。这一信息对于开发新的治疗方式也是至关重要的，这些治疗方式有可能阻止或延缓这些不同疾病条件和治疗对正常腺泡细胞功能的毒性作用。本项目的主要目的是在分子水平上研究和确定在腺泡细胞凋亡的起始信号传导和执行中起核心作用的两个主要细胞蛋白家族的确切功能。两个关键的调节蛋白家族是caspase和Bcl-2蛋白家族。我们将确定它们的表达水平、亚细胞分布、磷酸化水平和它们在特定凋亡刺激引起的腺泡细胞凋亡的开始和持续期间的功能活性。这些研究将使用大鼠腮腺和下颌下腺泡细胞的原代培养以及永生化大鼠腮腺和下颌下腺泡细胞系进行。这两个至关重要的蛋白家族的鉴定和表征将为抑制腺泡细胞异常凋亡的新治疗方法的开发提供新的基础科学信息和见解，长期目标是改善数百万受影响个体的生活质量。

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.