Signal transduction and salivary cell apoptosis

细胞程序性死亡或凋亡的改变有助于 发育异常、自身免疫性疾病和癌症。这是 最清楚地证明了这一发现，即Bc l-2在 在人类B细胞淋巴瘤发展中的作用。这也可能是 在唾液腺的情况下，唾液腺的发育是正确的 肿瘤可能涉及基因变化，刺激增殖和 抑制细胞凋亡。同样，干燥综合征似乎也涉及到 自身免疫反应导致唾液腺泡细胞丢失 Fas诱导的细胞凋亡。这些观察表明，理解 调节唾液腺细胞凋亡的信号机制是 对于了解这种组织的生物学来说是非常重要的。这项建议 将专注于两个不同的信号分子，MAP的成员 激酶家族，以及抗细胞凋亡的蛋白激酶AKT。基于我们的 依托泊苷诱导唾液细胞系凋亡的数据，我们假设 这会改变两个MAP激酶家族成员之间的平衡， ERK和JNK可能在决定一种 细胞将经历细胞凋亡。我们将确定这是否也是真的 对于另外两种凋亡刺激，Fas和x射线，使用这两种 已建立的唾液腺泡细胞系和原代唾液腺泡细胞。 不同类型的显性负性和成分激活突变体 信号分子将被用来确定ERK和JNK的作用 在细胞凋亡中。我们还假设AKT的激活，要么是通过 生长因子刺激或突变AKT，可抑制细胞凋亡 由依托泊苷、X-射线或Fas诱导。这将直接在 不同生长刺激的唾液细胞系和原代腺泡细胞 因子，或用腺病毒载体转导，编码结构性 AKT的激活突变体。最后，表达A基因的转基因小鼠 唾液腺中AKT的结构性激活形式将用于 确定AKT在抑制该组织中的细胞凋亡中所起的作用。 AKT表达对体内组织动态平衡的影响将是 评估过了。此外，我们还将研究特定细胞凋亡的影响。 这些转基因产物对唾液腺泡细胞的刺激作用 在活体内。这些研究将提供有关以下途径的信息 调节唾液腺泡细胞的凋亡是我们 对这种复杂组织的理解。

Alterations in programmed cell death or apoptosis contribute to developmental abnormalities, autoimmune disease, and cancer. This is most clearly demonstrated by the discovery that the Bcl-2 plays a critical role in the development of B-cell lymphoma in humans. This may also be true in the case of salivary gland where the development of salivary gland tumors might involve genetic changes that stimulate proliferation and suppress apoptosis. Likewise, Sjogrens syndrome appears to involve the loss of salivary acinar cells by an autoimmune response that results in Fas-induced apoptosis. These observation suggest that understanding the signaling me3chanisms that regulate apoptosis in the salivary gland is fundamental to understanding the biology of this tissue. This proposal will focus upon two different signaling molecules, members of the MAP kinase family, and the anti-apoptotic protein kinase AKT. Based upon our data on etoposide-induced apoptosis of salivary cell lines, we hypothesize that changes in the balance between two MAP kinase family members, ERKs and JNKs, may play an important role in determining whether a cell will undergo apoptosis. We will determine whether this is also true for two other apoptotic stimuli, Fas and x-irradiation, using both established salivary acinar cell lines and primary salivary acinar cells. Dominant negative and constitutively activated mutants of different signaling molecules will be used to determine the role of ERKs and JNKs in apoptosis. We also hypothesize that activation of AKT, either by growth factor stimulation or mutation of AKT, can suppress apoptosis induced by etoposide, x-irradiation, or Fas. This will be directed tested in salivary cell lines and primary acinar cells stimulated with various growth factors, or transduced with adenoviral vectors encoding a constitutively activated mutant of AKT. Finally, transgenic mice that express a constitutively activated form of AKT in the salivary gland will be used to determine the role that AKT plays in suppressing apoptosis in this tissue. The effects of AKT expression tissue homeostasis in vivo will be assessed. Furthermore, we will examine the effects of specific apoptosis stimuli upon salivary acinar cells from these transgenic both in vitro and in vivo. These studies will provide information about pathways that regulate apoptosis in salivary acinar cells which is fundamental to our understanding of this complex tissue.