Function of paired activating and inhibitory FCR signaling in immune regulation
Active Project Grant Awarded Last action
- Award ID
- F31AI200253
- Recipient
-
University Of California, Santa Barbara UEI G9QBQDH39DF4
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $97,528
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 0% complete
- Originally
- Place of performance
- Santa Barbara, CA 93106, USA
Award details come from USAspending.gov.
Description
- Abstract
- Recognition of secreted IGG by FC receptors (FCRS) on innate immune cells is critical for clearing pathogens by phagocytosis. However, overactive FCR signaling can damage healthy tissue. Macrophages, an innate immune cell type, regulate tissue homeostasis and pathogen clearance through immune effector functions including cytokine release, antibody-dependent cellular toxicity, antigen presentation, and phagocytosis. Macrophages express five itam-bearing activating FCRS, and a single itim-bearing inhibitory FCR: fcγriib. Misregulated fcγriib signaling is associated with chronic autoimmune conditions. From a systems-perspective, fcγriib is puzzling. If macrophages can simply downregulate activating FCR, why does fcγriib exist? Given that fcγriib uniquely shares the ligand of IGG with its cognate activating fcγrs, the dissection of its specific effects from the activating FCRS is particularly challenging. To solve this, we designed a synthetic receptor system that allows selective stimulation of fc𝛾riib and activating fc𝛾rs independently using DNA nanotechnology. Using this system, our preliminary data demonstrates that fcγriib stimulation does not inhibit a specific stage of phagocytosis but rather sets a time limit on the duration of the phagocytic attempt, thereby increasing the frequency of phagocytic failures. We confirmed that this effect required with recruitment of SHIP1, an inositol phosphatase known to complex with fcγriib's itim and dephosphorylate PI(3,4,5)P3 (PIP3), a key signaling lipid required for phagocytosis. Further, a computational model of phospholipid conversion during concurrent activating and inhibitory FCR signaling generates an incoherent feedforward loop that supports our in vivo observations. Therefore, the central hypothesis of this proposal is that fcγriib inhibits phagocytosis by enacting a phospholipid mediated time-limit on phagocytosis. To test this hypothesis, I will utilize genetically altered macrophages with fcγriib knocked out or overexpressed. In aim 1, I will test the hypothesis that the dramatically inhibited fcγriib phenotype is a result of decreased phagocytosis attempt durations through high resolution quantitative imaging analysis of timelapses capturing phagocytosis. In aim 2, I will demonstrate that differences in phagocytic attempt duration in macrophages with and without fcγriib signaling are mediated by changes to PIP3 dynamics at the progressing phagocytic cup. I will accomplish this with the use of a highly specific fluorescent PIP3 probe. Finally, aim 3 will provide insight into this inhibitory mechanism's role in controlling macrophage behavior in response to various IGG isotypes during different inflammatory contexts, by measuring both phagocytic timing and PIP3 dynamics during engulfment of targets opsonized with different IGG isotypes. Collectively, this work will establish fcγriib as a PIP3-driven molecular timer that enforces strict time limits on phagocytic persistence, resolving how its dysregulation causes pathogenic outcomes and providing mechanistic criteria to optimize therapeutic antibody isotype selection for tuning effector cell engagement.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $48,764 | |
| Amendment | $48,764 | |
| Original award | $0 |
Quick answers
Who received award F31AI200253?
F31AI200253 was awarded to University Of California, Santa Barbara by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on November 8, 2026.
How much is award F31AI200253 worth?
$97,528 has been obligated on F31AI200253.
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