MOLECULAR MECHANISMS OF SALIVARY ACINAR CELL APOPTOSIS

唾液腺的功能对维持正常的口腔健康很重要，在正常的消化中也起着关键作用。正常的唾液腺功能和体内平衡依赖于细胞生长、维持细胞分化和细胞死亡的平衡。美国有数百万人患有大小唾液腺的良恶性肿瘤和唾液腺功能减退。长期药物治疗可引起唾液腺功能减退，特别是在老年人、Sjorgen综合征、一种自身免疫性疾病、x射线照射和癌症化疗中。在这些疾病中，唾液腺功能可能因腺泡细胞的丧失或异常凋亡引起的腺稳态的丧失而受到损害。本项目的长期目标是提供必要的基础信息，以便在分子水平上充分了解唾液腺泡凋亡。这些基础科学信息的发展对于了解唾液腺肿瘤发生的分子基础，以及开发新的治疗方法来预防由异常凋亡引起的唾液腺功能减退至关重要。项目一将评估caspase和Bcl-2超家族在唾液腺泡凋亡中的作用。项目二将评估MAPK和Akt信号转导通路在调节腺泡凋亡中的作用。项目三将研究调节蛋白激酶C家族在抑制和/或增强基因毒性药物和细胞凋亡发生中的作用。对细胞内信号转导通路以及唾液腺泡凋亡的启动物和效应物的重要性的基本理解是开发治疗肿瘤发展中唾液腺功能减退的新治疗策略的第一步。

Salivary gland function is important in maintaining normal oral health, as well as playing a critical role in proper digestion. Normal salivary gland function and homeostasis is dependent upon the balance of cell growth, maintenance of cellular differentiation and cell death. Several million people in the United States suffer from benign and malignant tumors of the major and minor salivary glands and salivary gland hypofunction. Salivary gland hypofunction can be caused by chronic drug treatment, particularly in the elderly, Sjorgen's syndrome, an autoimmune disease, X-ray irradiation and cancer chemotherapy. In each of these disease conditions, salivary gland function may be compromised by the loss of the acinar cells or loss of glandular homeostasis due to aberrant apoptosis. The long range goal of this Program Project is to provide the fundamental information that is necessary to fully understand salivary acinar apoptosis at the molecular level. The development of such basic scientific information is essential in understanding the molecular basis of salivary gland tumor development and for the development of new therapeutic modalities for the treatment of prevention of salivary gland hypofunction caused by aberrant apoptosis. Project One will evaluate the role of the caspase and Bcl-2 superfamilies in salivary acinar apoptosis. Project Two will evaluate the role of the MAPK and Akt signal transduction pathways in regulating acinar apoptosis. Project Three will investigate the role of the protein kinase C family of regulatory proteins in suppressing and/or enhancing genotoxic agents and the onset of apoptosis. A fundamental understanding of how important intracellular signal transduction pathways along with the initiators and effectors of salivary acinar apoptosis is the first step in the development of new therapeutic strategies for the treatment of salivary gland hypofunction in neoplastic development.