# Mechanisms of immune dysregulation in human PI3Kgamma deficiency

> **NIH NIH R21** · YALE UNIVERSITY · 2020 · $209,375

## Abstract

Project Summary
 Primary immunodeficiency diseases (PIDs) have great potential to provide mechanistic insights into the
molecules and pathways fundamentally important for maintenance of human immune health, and the unbiased
nature of forward genetics makes these studies particularly exciting to pursue. The phosphoinositide 3-kinase
(PI3K) signaling pathway plays important roles in many aspects of cell behavior within and outside the immune
system. Both gain-of-function and loss-of-function mutations in the genes encoding the p110 and p85 PI3K
subunits have been identified in PID patients and have shed light on basic PI3K biology and underpinnings of
inherited immunodeficiency. However, no mutations in the other PI3K genes have been described in inherited
human disorders. We have now identified novel loss-of-function mutations in a new PI3K gene, PIK3CG, and
our preliminary studies highlight its importance in immune competence and regulation of tissue inflammation in
this disorder we have termed Inactivated PI3K Syndrome (IPGS). Using primary human cells and cutting-edge
`dirty' mouse modeling approaches that recapitulate human disease by combining genetic manipulation and
natural pathogen exposure, two specific aims will be pursued. Aim 1) To define the roles for PI3K in regulating
T cell-intrinsic and -extrinsic signals that modulate T cell activation and differentiation. Aim 2) To dissect the
mechanistic basis for antibody defects. The results of these investigations will provide significant insights into
this novel PID and PI3K signaling in general and will lay the groundwork to improve physiologically relevant
models for translational research in PIDs and other human disease contexts.

## Key facts

- **NIH application ID:** 9896405
- **Project number:** 1R21AI144315-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Carrie L. Lucas
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $209,375
- **Award type:** 1
- **Project period:** 2020-01-24 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896405

## Citation

> US National Institutes of Health, RePORTER application 9896405, Mechanisms of immune dysregulation in human PI3Kgamma deficiency (1R21AI144315-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9896405. Licensed CC0.

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