Genome organizer SATB1 function in salivary gland and development and growth

项目总结/摘要 唾液腺产生唾液，促进消化，作为吞咽食物的润滑剂，并防止 口腔感染和蛀牙。因此，唾液腺功能对口腔健康至关重要。目前， 对于受损的唾液腺没有有效的治疗方法， 头颈癌或自身免疫性疾病。为了在未来制定治疗策略， 了解唾液腺发育和再生的调控机制。小 是已知的基因表达，表观遗传学和染色质组织的唾液腺的调节。 在这里，我们将测试一个假设，即基因组组织者SATB 1是一个重要的调节器，在唾液腺 胚胎发育、出生后早期生长发育和功能。这一假设得到了支持 SATB 1蛋白在野生型小鼠出生后第12天（P12）在腺泡和导管细胞中表达 以及通过检测Satb 1-/-小鼠与野生型小鼠相比小得多的唾液腺。我们将确定 SATB 1蛋白表达细胞在胚胎和出生后发育的SG。通过遗传谱系追踪， 我们将研究SATB 1在腺泡细胞发育和功能中的作用。我们将删除腺泡细胞中的SATB 1- 特定时间点的特定细胞谱系（例如AQPT 5+或MIST 1+细胞），并确定SATB 1的作用 在他们的后代中进行消融。通过这些实验，我们将了解SATB 1在增殖中的作用， 胚胎和出生后早期发育期间的形态发生、存活和生长。此外，结合 使用全局连续测序（GRO-seq）的谱系追踪方法，它捕获新生转录本，我们 将以细胞谱系特异性和阶段特异性的方式鉴定由SATB 1调控的基因。我们预计 这些实验的结果将揭示SATB 1在唾液腺中的重要作用 发展、生长和功能，这些信息可能会为未来提供基础 促进唾液腺再生的治疗设计。

Project Summary/Abstract Salivary glands produce saliva, which facilitates digestion, acts as a lubricant to swallow foods, and prevents infections in oral cavity and tooth decay. Therefore, salivary gland function is important for oral health. Currently, there is no effective treatment for impaired salivary glands, which can be caused by therapeutic irradiation for the head and neck cancer or autoimmune diseases. To develop therapeutic strategies in the future, it is essential to understand the regulatory mechanisms underling development of salivary glands and their regeneration. Little is known about the regulators of gene expression, epigenetics and chromatin organization for salivary glands. Here, we will test a hypothesis that the genome organizer SATB1 is a critical regulator in salivary gland embryonic development, early postnatal growth and development, and function. This hypothesis is supported by SATB1 protein being expressed in both acinar and ductal cells at postnatal day 12 (P12) of wild-type mice and by detection of much smaller salivary glands in Satb1-/- mice compared to wild-type mice. We will identify SATB1 protein-expressing cells in SGs during embryonic and postnatal development. By genetic lineage tracing, we will study the role of SATB1 in acinar cell development and function. We will delete SATB1 in acinar cell- specific cell lineages (e.g. AQPT5+ or MIST1+ cells) at specific time points and determine the effects of SATB1 ablation in their descendants. Through these experiments, we will learn the roles of SATB1 in proliferation, morphogenesis, survival and growth during embryonic and early postnatal development. In addition, combining the lineage-tracing approach with Global run-on sequencing (GRO-seq), which captures nascent transcripts, we will identify genes regulated by SATB1 in a cell lineage-specific and stage-specific manner. We expect that results from these proposed experiments will uncover the critical contribution of SATB1 in salivary gland development, growth and function, and such information will likely provide the foundation for the future therapeutic design to promote salivary gland regeneration.