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Elucidating the mechanism of cell type specific regulation of the Par complex

阐明 Par 复合物的细胞类型特异性调节机制

基本信息

批准号：
10607140
负责人：
Elizabeth Vargas
金额：
$ 3.91万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10607140
关键词：
Adaptor Signaling Protein Affect Allosteric Regulation Animals Binding Biochemical Biochemistry and Cellular Biology Biological Assay Cell Extracts Cell Polarity Cell division Cell model Cell physiology Cells Cellularity Communication Complex Cues Data Defect Development Disease Doctor of Philosophy Education Elements Epithelial Cells Epithelium Exclusion Fellowship Foundations Functional disorder Future Health In Vitro Knowledge Length Link Mediating Mediator Mentorship Modeling Molecular and Cellular Biology Nature Organism PAR-6 protein Phosphorylation Phosphotransferases Process Protein Truncation Proteins Radiolabeled Regulation Reporting Repression Research Role Science Site Structure Switching Complex System Techniques Testing Training Work cell cortex cell motility cell type experience experimental study genetic regulatory protein in vivo innovation insight novel therapeutics polarized cell predictive modeling reconstitution spatiotemporal tumorigenesis

项目摘要

PROJECT SUMMARY/ ABSTRACT: This project provides the applicant with Ph.D. training in molecular and cellular biology and biochemistry. The applicant’s thesis research will further our understanding of how cell polarization is regulated during the development of multicellular organisms. Cell polarity, or the organization of cellular components to specific regions of the cell, is fundamental for diverse cellular processes such as asymmetric cell division and cell migration. At the core of cell polarity is the evolutionarily conserved Par complex, which guides the subcellular localization of downstream factors by phosphorylation. The Par complex phosphorylates a multitude of downstream factors, but only if strict spatial and temporal requirements are satisfied. While the enforcement of these spatiotemporal requirements is key to proper Par complex function, the field does not fully understand this process. This project will examine how two regulatory proteins, Par-3 and Cdc42, work in concert to mediate Par complex function. Subcellular localization of the Par complex at the cell cortex is regulated by Par-3, which inhibits Par complex activity as it asymmetrically targets it to the cortex. Once properly localized, the Par complex transitions from Par-3 to Cdc42, stimulating Par complex activity. Thus, the transition from Par-3 to Cdc42 is crucial for Par complex activity regulation. Although this transition is a central feature of current models of cell polarity in diverse cell types, the mechanism detailing how the Par complex transitions from an inactive Par-3- bound to an active Cdc42-bound complex remains unresolved. Additionally, the activity of these complexes has not been directly examined nor is the mechanism known for how Par-3 or Cdc42 regulate Par complex activity. The applicant’s preliminary biochemical data indicates that Par-3 and Cdc42 inhibit each other’s binding to the Par complex. The applicant will address several fundamental knowledge gaps in our understanding of Par mediated polarity using a wide range of biochemical techniques. The applicant will resolve which inter and intramolecular interactions control the Par complex’s ability to switch from a Par-3 to Cdc42 (Aim 1), investigate how Par complex switching is regulated diverse cell types by examining the role of the cell type specific Par complex regulator, Crumbs (Aim 2), and test the hypothesis that Par-3-bound Par complex is less catalytically active than Cdc42- or Crumbs-bound Par complex (Aim 3). Together, the proposed aims will provide a thorough mechanistic understanding for how the Par complex localization and activity is regulated in different cellular contexts. Characterizing this critical regulatory axis will provide insight for developmental defects and disease which have been linked to Par-mediated polarity dysfunction. The applicant will receive extensive technical training guided by an experienced mentorship team. Additionally, this fellowship will provide the applicant with science communication, educational, and professional development opportunities.

项目摘要/摘要：