ISAC Award Program Application Concept

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Mechanism of neutrophil granule biogenesis
Julia von Blume   (New Haven, CT)
Professional secretory cells possess granules that store enzymes, signaling molecules, and host defense proteins. These granules can fuse with the plasma membrane in response to extracellular stimuli, a phenomenon termed regulated secretion. A prime example is the pancreatic beta cell which utilizes one class of dense-core vesicles to amass significant quantities of insulin. In contrast, neutrophils, another class of professional secretory cells, exhibit three distinct granule types characterized by their protein composition and ability to fuse with the plasma membrane. This regulated exocytosis of granules is pivotal in transforming dormant neutrophils into fully activated counterparts, allowing them to execute functions such as chemotaxis, phagocytosis, and eradication of bacteria. However, the exact molecular mechanisms governing the biogenesis of neutrophil granules remain elusive, thereby restricting the development of interventions for neutropenic disorders. Consequently, gaining a deeper understanding of the molecular underpinnings of granule disorders could lead to the creation of potent and broadly effective therapeutic strategies. Our unpublished results have shown that serglycin, chromogranin A, and chromogranin B play key roles in forming distinct granule subtypes during neutrophil differentiation. With this in mind, the current proposal aims to delve further into the characterization of these components, elucidate their specific molecular functions in the process of granule biogenesis, and assess their significance in the overall role of neutrophils. At the core of my research laboratory's interests lie the fundamental concepts of organellar biogenesis, protein trafficking, and secretion. Additionally, thanks to our established collaboration with Dr. Shangqin Guo, a distinguished authority in granulocyte and macrophage progenitors, a member of the Yale Cooperative Center of Excellence in Hematology (YCCEH), and the Yale Stem Cell Center, we are poised to delve into the mechanisms governing granule formation in hematopoietic cells. As the Associate Director of the Imaging Core within the YCCEH, Dr. Guo will generously provide guidance and facilitate access to the resources of the core facility. The successful execution of this investigation has the potential to uncover the foundational principles governing granule biogenesis during granulopoiesis, potentially yielding innovative and efficacious treatment strategies for neutropenia and granule-related deficiencies unique to neutrophils.
Data for this report has not yet been released.

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