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.

Public Health Relevance

Identifying and understanding the underlying causes of inherited immune disorders is an important scientific goal because of the potential to not only solve and better treat disease in these rare individuals but also to provide key insights into fundamental human biology. These insights can then be used to devise new and better-informed therapies for more common diseases with public health relevance including allergy, asthma, infection, autoimmunity, etc. The goal of this proposal is to investigate the mechanistic link between inherited mutations in a novel PI3K gene and pathological immune processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI144315-01A1
Application #
9896405
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Voulgaropoulou, Frosso
Project Start
2020-01-24
Project End
2021-12-31
Budget Start
2020-01-24
Budget End
2020-12-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code