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Impact of a Disease-Associated Dynactin Variant on Motile Phenomena in Lung Epithelial Cells

疾病相关的 Dynactin 变体对肺上皮细胞运动现象的影响

基本信息

批准号：
10704306
负责人：
TRINA A SCHROER
金额：
$ 36.69万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10704306
关键词：
Actins Acute Respiratory Distress Syndrome Affect Behavior Binding Biochemical Biochemistry Biological Assay Biosensor Biotinylation Cell Adhesion Cell membrane Cell physiology Cell surface Cells Cellular biology Characteristics Complement Coupled Cues Cystic Fibrosis Cytoskeleton Data Defect Detection Disease Disease Progression Dynein ATPase Epithelial Epithelial Cells Event Fibrosis Focal Adhesion Kinase 1 Focal Adhesions Genes Genetic Genetic Transcription Goals Guanine Guanine Nucleotide Exchange Factors Human Human Cell Line Image Integrins Lead Link Lung Lung Adenocarcinoma Lung diseases Maintenance Membrane Mesenchyme Methods Microscopy Microtubules Mitosis Motor Movement Pathology Phase Phenotype Plus End of the Microtubule Positioning Attribute Process Proteins Proteome Proteomics Pulmonary Pathology Receptor Protein-Tyrosine Kinases Risk Role Secretory Vesicles Sepsis Signal Pathway Signal Transduction Sorting - Cell Movement Surface Total Internal Reflection Fluorescent Transitional Epithelium Variant Work assault base bronchial epithelium cell cortex cell motility cofactor cohort contrast imaging crosslink cytokine dynactin ephexin exome sequencing experimental study imaging study in vivo insight interest lung repair macromolecular assembly migration monolayer novel protein transport repaired response rho GTP-Binding Proteins stem tool trafficking tumor wound wound healing

项目摘要

Project Summary The microtubule-based motor, cytoplasmic dynein-1, is best known for providing motile functions in membrane trafficking and mitosis. Complete abrogation of dynein function yields gross cellular and organismal defects that preclude detection of its contributions to other important cellular phenomena. The work described in this proposal focuses on a human dynein variant, DCTN4Y270C, that is associated with increased risk of extreme lung pathology. DCTN4Y270C (rs35772018) was first identified as a genetic modifier of cystic fibrosis but has also been associated with increased risk of lung adenocarcinoma and acute respiratory distress syndrome following sepsis. Homozygous DCTN4Y270C has no obvious impact on its own, indicating that any defects associated with DCTN4Y270C exacerbate pathology but do not cause it directly. Lung epithelial cells must be able to undergo a reversible epithelial-mesenchyme transition (EMT) to provide the ongoing wound-healing that is required for repair and maintenance of the airway. Imbalance in reversible EMT is believed to underlie the fibrosis seen in severe lung disease. Phenotypically, DCTN4Y270C expression yields reduced cell movement into experimental wounds and facilitates acquisition of epithelial polarity, both hallmarks of the mesenchyme-epithelial transition (MET). Transcriptionally, cultured bronchial epithelial cells expressing DCTN4Y270C show with hallmarks characteristic of EMT. These incongruent findings indicate that DCTN4Y270C positions cells in an aberrant, yet tolerated, state that lies between epithelia and mesenchyme, similar to the partial EMT seen in tumors. The overarching goal of the proposed work is to understand how DCTN4Y270C affects lung cell biology, specifically the cytoskeleton- dependent phenomena that underlie directed cell migration. To obtain mechanistic insight into how DCTN4Y270C alters cell function we determined the interactomes of DCTN4WT and DCTN4Y270C using BioID proximity biotinylation. This revealed a small cohort of differential interactors that others have linked to the phenomena we know to be altered in cells expressing DCTN4Y270C. The aims of this project are to establish mechanistic connections between dynein/dynactin and these novel interactors, taking advantage of DCTN4Y270C as a unique tool for modulating and perturbing cell function.

项目总结