Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY Neutrophils are crucial players in the innate immune response arm. They rapidly migrate to sites of inflammation where they perform various effector functions critical for combating infections such as degranulation, generate reactive oxygen species, and release neutrophil extracellular traps. Tipping the balance of inflammation as seen in neutropenia, neutrophilia, or aberrant neutrophil functions lead to recurrent infections or inflammatory diseases. Therefore, it is important to understand the mechanisms that regulate these functions to identify targets for therapeutics. Proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2) has been identified as one such protein that regulate neutrophil function. It is highly expressed in neutrophils, yet its exact role in neutrophil biology is unclear. This proposal aims to investigate the functional significance of PSTPIP2, and the mechanism involved in its regulation of neutrophil function and development. My preliminary data shows that mice lacking PSTPIP2 (Pstpip2cmo mice) display an intriguing phenotype characterized by an increased number of neutrophils in the bone marrow, blood, and spleen. Upon further examination, I found that the number of granulocyte progenitors in the bone marrow is also increased in these mice compared to wild-type mice. Furthermore, Pstpip2cmo neutrophils exhibit hyperinflammatory behavior, secreting higher levels of interleukin-1β (IL-1β) and reactive oxygen species (ROS) upon stimulation (in vitro) and are more efficient at bacterial clearance (in vivo). Based on my preliminary data, I hypothesize that PSTPIP2 regulates differentiation of granulocyte progenitors into neutrophils and plays an inhibitory role in inflammatory mediator release through its interaction with the cytoskeleton. To address the knowledge gaps in understanding the underlying mechanism, I propose two specific aims: 1) I will investigate how PSTPIP2 influences granulocyte progenitor differentiation into neutrophils. This aim will elucidate the role of PSTPIP2 in controlling neutrophil development by utilizing single-cell RNA sequencing, flow cytometry, and progenitor colony forming assays. 2) I aim to understand how PSTPIP2 influences neutrophil effector functions in response to inflammatory stimuli. PSTPIP2's known role in regulating membrane dynamics in macrophages points to its potential involvement in actin cytoskeleton rearrangement, which could inhibit neutrophil effector functions and decrease bacterial killing capabilities. This research will uncover novel mechanisms governing neutrophil development and functions which can identify targets for treating infectious and inflammatory disorders and shedding light on the pathogenesis of autoinflammatory conditions, aligning with NIH's goal of advancing knowledge to improve human health and underscoring my commitment to immunology research.
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