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Modulation of Acute Lung Injury by the Phosphatase SHP1

Award Number: K08HL177269
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/02/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Modulation of Acute Lung Injury by the Phosphatase SHP1 - PROJECT SUMMARY The acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality and neutrophils are critical to its pathogenesis. Neutrophil activation is regulated by inhibitory tyrosine phosphatases including the Src homology region 2 domain-containing phosphatase-1 (SHP1). SHP1 mutations are associated with severe pediatric lung disease and early onset COPD, the former is a recent novel observation by our research group. I have published data that neutrophil SHP1 prevents hemorrhage and hyperinflammation in acute lung injury (ALI) after LPS challenge or P.aeruginosa infection and pharmacologic activation of SHP1 reduces lung inflammation in the setting of ALI. SHP1-dependent intra-cellular signaling limiting hyperinflammation and pulmonary hemorrhage is unknown. I propose the central hypothesis that SHP1 mutations associated with reduced phosphatase activity will have allele-specific hyperinflammation with distinct phospho-proteomic profiles, and pharmacologic activation of SHP1 will reduce lung injury. To test this hypothesis, I will utilize recently generated novel SHP1 allelic series mice containing patient identified mutations. Aim 1 – Determine the role of SHP1 in acute lung inflammation through analysis of SHP1 allelic series mice using pre-clinical models of ALI coupled with mass spectrometry-based proteomics. Aim 2 – Test the hypothesis that pharmacologic activation of SHP1 reduces inflammation in the setting of ALI. Significance of the Results – The proposal will reveal the immunoregulatory role of SHP1 in ALI, guide the development of SHP1 activating compounds and lay the foundation for precision pharmacotherapies for patients with hyperinflammation associated lung injury. Career Development Plan – The proposed project and training plan will lay the foundation for my transition to an independent physician-scientist studying the role of immune regulating phosphatases in lung injury and inflammation. The plan involves didactics, conference attendance, mentorship, and hands-on training by experienced and highly successful primary mentor physician-scientists, in addition to expert collaborators and an experienced career advisory committee. Environment – Training will be at UCSF, which is an ideal environment that supports physician-scientists. The UCSF Department of Pediatrics has a long track record of fostering the career development of young faculty. UCSF is a highly collaborative institution and both mentors are members of the UCSF Immunology Program, which is highly regarded worldwide.


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: 2026 ( Subtotal = $174,744 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	1	6/4/2026	NEW	$174,744
														Subtotal = $174,744

Grand Total All Awards = $174,744

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Modulation of Acute Lung Injury by the Phosphatase SHP1

Award Number: K08HL177269

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/02/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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