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：
10554239
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/10554239
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 Dry Eye Syndromes Duct (organ) structure Ductal Epithelial Cell Elderly Experimental Genetics Film Focal Adhesions Functional disorder Genetic Genetic Transcription Gland Goals Homeostasis Lacrimal gland structure Mediating Molecular Morphogenesis Mutant Strains Mice Nuclear Pathway interactions Persons 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 chemical genetics corneal epithelium gain of function gland development inducible Cre 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.

项目概要管状腺泡网络是泪腺结构的决定性特征，这对于泪腺的撕裂至关重要产生函数。然而，人们对这种结构是如何在分子水平上构建的知之甚少。这该项目将研究非受体酪氨酸激酶 Csk 在泪腺管腔形成中的新作用和细胞分化。通过生成可诱导的小鼠突变体，我们将定义时间和谱系特异性 Csk 在腺泡和导管细胞中的功能。使用功能获得和功能丧失方法，我们寻求证明 Src 家族激酶介导泪腺中的 Csk 信号传导。我们还将设立一个化学遗传系统检查 Csk 急性失活后的粘着斑复合物并建立细胞骨架信号传导在介导泪腺发育中 Csk 功能中的作用。最后，我们将阐明 Csk 信号传导调节细胞转录组的机制。泪腺功能障碍是水液缺乏性干眼病的根本原因，该病困扰着数百万人。经过阐明Csk生成泪腺的机制，将为基于细胞的开发提供信息干眼病的治疗。