Mechanism of Csk signaling in lacrimal gland morphogenesis

Csk信号在泪腺形态发生中的机制

基本信息

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
项目类别：
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

项目摘要

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 Tubulo-Acinar网络是泪腺结构的定义特征，这对于其撕裂至关重要产生功能。但是，关于这种体系结构是如何在分子水平构建的，知之甚少。这项目将研究非受体酪氨酸激酶CSK在泪腺流体形成和细胞分化。通过产生诱导小鼠突变体，我们将定义特定的时序和谱系 CSK在腺泡和导管细胞中的功能。使用功能丧失方法，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系统以检查CSK急性失活后局灶性粘附复合物细胞骨架信号在介导CSK功能在泪腺发育中的作用。最后，我们会的阐明CSK信号调节细胞转录组的机制。泪腺功能障碍是造成水不足的干眼疾病的根本原因，这会折磨数百万人。经过阐明CSK在产生泪腺时的机制，它将告知基于细胞的发展干眼症的治疗。