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

BCL-2 和 caspase 家族在腺泡细胞凋亡中的作用

• 批准号: 6564070
• 负责人: David O Quissell
• 金额: $ 13.09万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564070
• 关键词: BCL2 gene /protein; acinar cell; apoptosis; cysteine endopeptidases; laboratory mouse; laboratory rat; phosphorylation; protein localization; salivary glands; tissue /cell culture

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.

唾液腺功能减退是一个主要的口腔健康问题，影响了美国数百万人的生活质量。多种情况可导致唾液腺泡细胞分泌功能的丧失，包括系统性疾病如舍格伦综合征（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、药物诱导的口干症和口腔癌。所有这些疾病状况或治疗都有可能改变正常的唾液腺腺泡细胞稳态并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。这些信息对于开发新的治疗方式也是必不可少的，这些治疗方式有可能阻断或延迟这些各种疾病状况和治疗对正常腺泡细胞功能的毒性作用。该项目的主要目标是在分子水平上研究和确定两个主要细胞蛋白家族的精确功能，这两个蛋白家族在腺泡细胞凋亡的启动信号传导和执行中起着核心作用。两个关键的调节蛋白家族是胱天蛋白酶和Bcl-2蛋白家族。我们将确定它们的表达水平，亚细胞分布，磷酸化水平和它们的功能活性在特定的凋亡刺激引起的腺泡细胞凋亡的发病和持续时间。将使用大鼠腮腺和下颌下腺泡细胞以及永生化大鼠腮腺和下颌下腺泡细胞系的原代培养物进行这些研究。这两个至关重要的蛋白质家族的鉴定和表征将为开发抑制异常腺泡细胞凋亡的新治疗方法提供新的基础科学信息和见解，其长期目标是改善数百万受影响个体的生活质量。