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Modulating kinase signaling in pulmonary fibroblasts

Award Number: F32HL184606
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/15/2026
PERIOD OF PERFORMANCE END DATE: 12/14/2027

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Modulating kinase signaling in pulmonary fibroblasts - Project Summary / Abstract Pulmonary fibrosis (PF) is a devastating disease process where the lung replaces functional tissue with scar, causing disability and death. Current therapeutics have modest benefit and are difficult for patients to tolerate. Kinase inhibitors have been tested in clinical trials for PF and several candidates have shown early phase efficacy but were not developed further due to systemic toxicity. In this proposal, we aim to develop antibody-drug conjugates (ADCs) with the goal of specifically targeting small molecule kinase inhibitors and kinase directed molecular glue degraders to pathogenic fibroblasts. We hypothesize that ADCS will specifically target kinase inhibition to fibroblasts or fibroblast subsets in pulmonary fibrosis and will thus allow the development of safer and more effective treatments. To identify methods to target fibroblasts specifically, we used data from single cell transcriptomics to precisely characterize collagen producing cell subpopulations in murine lung injury models. We identified multiple fibroblast subsets with distinct anatomical localization and variable activation of profibrotic pathways enabling migration, proliferation, and collagen production. We hypothesize that these subpopulations are directly responsible for pathogenic tissue fibrosis, and that specifically targeting all fibroblasts or subpopulations that emerge in PF could improve the therapeutic window of candidate drugs. We have identified cell surface expression proteins broadly expressed by fibroblasts or specifically induced in emergent subpopulations, cross- referenced them to proteomics data, and synthesized published antibodies against these targets. We have selected five kinase signaling pathways that are shown to be aberrantly regulated and functionally important in PF with effective inhibitors limited by systemic toxicity. We will use a well validated synthetic route for cleavable self-immolative linkage to antibody. Of these inhibitors, two are scaffolds for commercially available molecular glue degraders which we will test individually and conjugated to ADCs. We will first test ADCs in vitro in proliferation, migration, and collagen production assays. We will subsequently test the most potent ADCs in a murine model of pulmonary fibrosis and in precision-cut lung slices from patients with idiopathic pulmonary fibrosis. We anticipate that these ADCs will have improved efficacy and toxicity profiles. At completion, this project will generate novel antibody-drug conjugates for the study of fibroblasts and fibroblast subpopulations in pulmonary fibrosis. The data generated from these tools will provide mechanistic insights into the roles these cells play in pulmonary fibrosis, complementing existing genetic tools. In the longer term, we will apply this paradigm to the development of cell type specific therapies for pulmonary fibrosis, which will represent a new avenue for cell- and organ- specific targeted therapeutics for this currently incurable disease.


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 = $87,148 )
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	6/19/2026	NEW	$87,148
														Subtotal = $87,148

Grand Total All Awards = $87,148

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Modulating kinase signaling in pulmonary fibroblasts

Award Number: F32HL184606

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/15/2026

PERIOD OF PERFORMANCE END DATE: 12/14/2027

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