Thursday, May 2, 2024
5/2/2024
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.
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