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.

项目摘要 小管-腺泡网络是泪腺结构的定义特征，这对于泪腺撕裂至关重要 生产功能。然而，很少有人知道这种结构是如何在分子水平上构建的。的 该项目将研究非受体酪氨酸激酶Csk在泪腺腔形成中的新作用， 细胞分化通过产生可诱导的小鼠突变体，我们将确定时间和谱系特异性 Csk在腺泡和导管细胞中的功能。使用功能增益和功能损失方法，我们寻求 证明Src家族激酶介导泪腺中的Csk信号传导。我们还将建立一个 化学遗传学系统检测Csk急性失活后的粘着斑复合物， 泪腺发育中细胞骨架信号在介导Csk功能中的作用。最后我们将 阐明Csk信号调节细胞转录组的机制。泪腺 功能障碍是困扰数百万人的水缺乏性干眼病的根本原因。通过 阐明Csk在泪腺发生中的作用机制，将为细胞基础的 治疗干眼病。