Mechanism of Csk signaling in lacrimal gland morphogenesis

Csk信号在泪腺形态发生中的机制

• 批准号: 9913637
• 负责人: Xin Zhang
• 金额: $ 40.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913637
• 关键词: Ablation; Acinar Cell; Acinus organ component; Actins; Acute; Adaptor Signaling Protein; Architecture; Atrophic; Cell Differentiation process; Cell Therapy; Cells; Complex; Cytoskeleton; Data; Development; Disease; Duct (organ) structure; Ductal Epithelial Cell; Elderly; Eye diseases; Film; Focal Adhesions; Functional disorder; Genetic; Genetic Transcription; Gland; Goals; Homeostasis; Lacrimal gland structure; Mediating; Molecular; Morphogenesis; Mutant Strains Mice; Nuclear; Pathway interactions; Phenotype; Phosphorylation; Population; Production; Protein Tyrosine Kinase; Regenerative Medicine; Resistance; Role; Signal Transduction; Specific qualifier value; Structure; System; Tamoxifen; Testing; Thinness; Time; Transcriptional Regulation; aged; aqueous; base; chemical genetics; corneal epithelium; experimental study; eye dryness; gland development; loss of function; molecular marker; mutant; novel; ocular surface; regenerative therapy; repaired; single-cell RNA sequencing; src-Family Kinases; transcriptome

PROJECT SUMMARY The tubulo-acinar network is the defining feature of the lacrimal gland structure, which is critical for its tear producing function. However, little is known on how this architecture is constructed at the molecular level. The project will investigate the novel role of non-receptor tyrosine kinase Csk in lacrimal gland lumen formation and cell differentiation. By generating inducible mouse mutants, we will define the timing and lineage specific function of Csk in acinar and ductal cells. Using both gain- and loss-of-function approaches, we seek to demonstrate that Src family kinases mediate Csk signaling in the lacrimal gland. We will also establish a chemical genetic system to examine the focal adhesion complex after acute inactivation of Csk and establish the role of cytoskeletal signaling in mediating Csk function in lacrimal gland development. Finally, we will elucidate the mechanism by which Csk signaling regulates the cellular transcriptome. Lacrimal gland dysfunction is the underlying cause of aqueous deficient dry eye diseases, which afflict millions of people. By elucidating the mechanism of Csk in generating the lacrimal gland, it will inform the development of cell based therapy for dry eye diseases.

项目总结 小管腺泡网络是泪腺结构的主要特征，这是泪腺撕裂的关键。 生产函数。然而，关于这种结构是如何在分子水平上构建的，人们知之甚少。这个 该项目将研究非受体酪氨酸激酶CSK在泪腺腔形成和泪腺发育中的新作用。 细胞分化。通过产生可诱导的小鼠突变，我们将定义特定的时间和谱系 CSK在腺泡细胞和导管细胞中的作用。使用增益和损失函数的方法，我们寻求 证明了Src家族激酶在泪腺中介导CSK信号转导。我们还将建立一个 检测CSK急性失活后焦点黏附复合体的化学遗传系统并建立 细胞骨架信号在泪腺发育中调节CSK功能中的作用。最后，我们会 阐明CSK信号调节细胞转录组的机制。泪腺 功能障碍是房水缺乏的干眼病的根本原因，这些疾病折磨着数百万人。通过 阐明CSK在泪腺发生中的作用机制，将为泪腺细胞的发育提供信息。 干眼症的治疗。