Tuesday, September 30, 2025 9/30/2025

Vesicular trafficking mechanisms regulating granulocyte function

Award Number: R01HL088256
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/03/2008
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Vesicular trafficking mechanisms regulating granulocyte function - Project Summary: Intracellular vesicular transport is essential for all aspects of neutrophil physiology and defects in this mechanism leads to disease in humans. In neutrophils, vesicular trafficking is associated with the processes of exocytosis, phagocytosis, signaling and NETs production; however, the molecular mechanisms that regulate mobilization of the different neutrophil secretory organelles require further elucidation. We have identified several key regulators of neutrophil granule trafficking, including the small GTPase Rab27a and its effectors JFC1 and Munc13-4. We have now identified WASH as a neutrophil factor that regulates cytoskeleton remodeling, vesicular trafficking and phagosomal maturation. Furthermore, we have pioneered the development of systems biology approaches to analyze vesicular dynamics and actin remodeling in granulocytes. Finally, we have identified a novel mechanism of late endosomal maturation that involves the interaction between the calcium sensor Munc13-4 and the late endosomal SNARE protein syntaxin 7 (STX7), to regulate TLR9 signaling and downstream neutrophil functions. Here, we use innovative quantitative methods to elucidate the mechanisms regulating vesicular transport associated with exocytosis, phagocytosis, late endosomal maturation and NETs production in neutrophils. We also propose to use our newly designed small-molecule inhibitors of Rab27a-JFC1 and Munc13-4-STX7 binding to investigate mechanisms of vesicular transport and to elucidate neutrophil function in disease using in vivo models of systemic inflammation and infection. The central goal of this grant is to elucidate the vesicular transport mechanisms that govern neutrophil pro-inflammatory processes, develop translational approaches to interfere with these processes and provide preclinical validation for their use to attenuate systemic inflammation. Since dysregulated neutrophil activation is injurious to the host and neutrophil secretory proteins play fundamental roles in the damage to the endothelium associated with endotoxemia, sepsis and sterile inflammation, these studies have important physiological significance and potential clinical applications. We hypothesize that the differential regulation of vesicular transport by Rab27a and its effectors is an essential mechanism to determine specific neutrophil functions and responses to insult. We also propose that small-molecule modulators of specific vesicular transport pathways will prevent some of the deleterious consequences of neutrophil activation during systemic inflammation. To test our hypotheses we propose the following Specific Aims: 1) Define the mechanisms that differentially regulate vesicular trafficking, actin-dependent propulsion and blockage of neutrophil granule subsets during phagocytosis and NETosis; 2) Establish the molecular mechanisms of mitochondrial nucleic acid-sensing by endosomal TLR signaling in neutrophils; 3) Develop mechanistic and translational approaches to decrease neutrophil-mediated systemic inflammation without affecting the innate immune response. The proposed research will elucidate the molecular mechanisms regulating neutrophil vesicular transport and lead to new strategies to treat inflammatory diseases.


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 = $727,183 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	001	15	8/15/2025	NON-COMPETING CONTINUATION	$727,183
2025	2021	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	12	1/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $727,183

Issue Date FY: 2024 ( Subtotal = $712,639 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	14	8/15/2024	NON-COMPETING CONTINUATION	$712,639
														Subtotal = $712,639

Issue Date FY: 2023 ( Subtotal = $715,326 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	001	13	8/17/2023	COMPETING CONTINUATION	$715,326
2023	2020	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	11	8/9/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $715,326

Issue Date FY: 2021 ( Subtotal = $483,750 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	12	5/14/2021	NON-COMPETING CONTINUATION	$483,750
2021	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	001	11	8/2/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $483,750

Issue Date FY: 2020 ( Subtotal = $917,750 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	001	11	8/10/2020	SUPPLEMENT FOR EXPANSION	$434,000
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	11	4/23/2020	NON-COMPETING CONTINUATION	$483,750
														Subtotal = $917,750

Issue Date FY: 2019 ( Subtotal = $483,750 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	10	5/29/2019	NON-COMPETING CONTINUATION	$483,750
														Subtotal = $483,750

Issue Date FY: 2018 ( Subtotal = $483,750 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	9	3/12/2018	COMPETING CONTINUATION	$483,750
2018	2016	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	001	8	6/12/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $483,750

Issue Date FY: 2016 ( Subtotal = $481,250 )
2016	2016	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	8	4/13/2016	EXTENSION WITH OR WITHOUT FUNDS	$481,250
														Subtotal = $481,250

Issue Date FY: 2015 ( Subtotal = $466,643 )
2015	2015	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	7	3/25/2015	NON-COMPETING CONTINUATION	$466,643
														Subtotal = $466,643

Issue Date FY: 2014 ( Subtotal = $464,275 )
2014	2014	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	6	4/30/2014	NON-COMPETING CONTINUATION	$464,275
														Subtotal = $464,275

Issue Date FY: 2013 ( Subtotal = $451,010 )
2013	2013	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	001	5	7/18/2013	COMPETING CONTINUATION	$451,010
2013	2012	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	4	7/18/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $451,010

Issue Date FY: 2012 ( Subtotal = $473,750 )
2012	2012	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	001	4	3/9/2012	NON-COMPETING CONTINUATION	$47,375
2012	2012	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	4	11/18/2011	NON-COMPETING CONTINUATION	$426,375
														Subtotal = $473,750

Issue Date FY: 2011 ( Subtotal = $473,750 )
2011	2011	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	3	11/23/2010	NON-COMPETING CONTINUATION	$473,750
														Subtotal = $473,750

Issue Date FY: 2010 ( Subtotal = $473,750 )
2010	2010	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	2	11/25/2009	NON-COMPETING CONTINUATION	$473,750
														Subtotal = $473,750

Issue Date FY: 2009 ( Subtotal = $473,750 )
2009	2009	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	1	12/3/2008	NEW	$473,750
														Subtotal = $473,750

Grand Total All Awards = $8,282,326

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Vesicular trafficking mechanisms regulating granulocyte function

Award Number: R01HL088256

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/03/2008

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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