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Genetic dissection of cytolytic exocytosis from natural killer cells

Award Number: R03AI178109
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/24/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Genetic dissection of cytolytic exocytosis from natural killer cells - PROJECT SUMMARY Natural killer (NK) cells are effector lymphocytes in the innate immune system. They destroy transformed and pathogen-infected cells mainly through secreting the contents of membrane-enclosed cytolytic granules, secretory lysosomes containing the pore-forming protein perforin and the serine proteases granzymes. When a NK cell recognizes its target cell, the contact area between the NK cell and the target cell forms a highly organized structure known as the immunological synapse. Cytolytic granules then migrate toward the immunological synapse, where they fuse with the plasma membrane to release their cytolytic molecules, a process known as cytolytic granule exocytosis. Once released from the NK cell, cytolytic molecules enter the target cell and trigger cell death. Imbalances in cytolytic molecule exocytosis cause major forms of human disorder such as immunodeficiency and chronic pathogen infection. The molecular basis of cytolytic granule exocytosis in NK cells is still poorly understood. The proposed research aims to bridge this knowledge gap. In our preliminary studies, we established an assay to quantify cytolytic granule exocytosis in a physiologically relevant NK-like cell line. Furthermore, we developed new platforms to genetically dissect complex exocytic pathways in mammalian cells using unbiased CRISPR screens. In this research, we will take strategic advantage of these assays to dissect cytolytic molecule exocytosis in NK cells using a genome-wide CRISPR screen. Next, we will validate the candidate genes identified in the screen using a pooled secondary screen. Finally, we will validate selected candidate genes using individual gene knockout. If successfully accomplished, this proposed research will offer the first genome-scale view of the cytolytic exocytic pathway and will significantly broaden our knowledge of NK cell functions. Insights acquired from this work will facilitate the development of novel therapeutic strategies for immune diseases caused by defective cytolytic granule exocytosis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $75,660 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	2	11/26/2024	NON-COMPETING CONTINUATION	$75,660
														Subtotal = $75,660

Issue Date FY: 2024 ( Subtotal = $78,000 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	001	1	9/11/2024	NEW	$7,800
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	1	1/24/2024	NEW	$70,200
														Subtotal = $78,000

Grand Total All Awards = $153,660

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Genetic dissection of cytolytic exocytosis from natural killer cells

Award Number: R03AI178109

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/24/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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