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Modulating signaling pathways in the fibrotic lung using synthetic biology tools

Award Number: K08HL186457
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/15/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Modulating signaling pathways in the fibrotic lung using synthetic biology tools - PROJECT SUMMARY/ABSTRACT Candidate: The applicant, Anjali Jacob, MD/PhD, is a pulmonary/critical care physician at UCSF with a long- term goal to lead an independent laboratory-based research program focused on developing synthetic biology tools to study and treat lung disease. The K08 application is key for her career development, providing her with (1) advanced training in synthetic biology methods for modulation of cell signaling, (2) mouse models and patient tissue models for studying basic mechanisms of pulmonary fibrosis and Tgf- signaling, (3) mentorship from a diverse team of scientists and physician-scientists to prepare her for independent R01 applications. Research: Idiopathic pulmonary fibrosis (IPF) is a deadly, incurable disease which that continues to have poorly defined mechanisms. New tools to study and treat IPF are needed. Activation of the TGF- signaling pathway is known to be important in driving pulmonary fibrosis, but the specific cell types responsible for disease progression are less well defined. The core hypothesis of this proposal is that cell-based delivery of TGF inhibitors will enable lung-cell or lung fibrotic-cell specific inhibition of TGF- signaling, providing a new tool for researchers to use to modulate signaling pathways including but not limited to TGF- to study and treat IPF and other chronic lung diseases. This proposal will characterize how using different cell-delivery methods to deliver TGF- inhibitors in the context of mouse models of pulmonary fibrosis and human IPF tissues influences TGF- signaling in specific lung cells. Aim 1 will test anti-RAGE (receptor for advanced glycation endproducts) synthetic notch receptor-based delivery that will target TGF- inhibitors to all lung cells. Aim 2 will test anti-tenascin C domain D (TNC-D) chimeric antigen receptor (CAR) that will target TGF- inhibitors to regions of fibrosis. Aim 3 will test a circuit in which anti-RAGE synthetic notch receptors drive expression of fibrosis targeting CAR-T cells (such as anti-TNC-D CAR) that will persistently deliver TGF- inhibitors only to regions of fibrosis within the lung and lead to longer term TGF inhibition by limiting T cell exhaustion. This work will provided key insights into how targeted, real-time modulation of TGF- signaling shapes pulmonary fibrosis in vivo and will establish a foundation for future mechanism-based cell therapies for lung disease. Mentorship and Training: Dr. Jacob’s training will be accomplished through formal coursework and under direct mentorship of world leaders including Dr. Dean Sheppard who has extensive expertise in molecular mechanisms of pulmonary fibrosis and TGF- signaling and Dr. Wendell Lim, a world-renowned researcher in modular signaling platforms, synthetic biology and cellular therapy. Dr. Sheppard and Dr. Lim have each mentored 40+ postdoctoral fellows including many physician scientists with independent laboratories and have been collaborating with Dr. Jacob on this program for the past 2.5 years. Environment: The candidate’s training will occur at the University of California, San Francisco, which has a history of transformative basic science research in both pulmonary biology and synthetic biology.


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	6/15/2026	NEW	$174,744
														Subtotal = $174,744

Grand Total All Awards = $174,744

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Modulating signaling pathways in the fibrotic lung using synthetic biology tools

Award Number: K08HL186457

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/15/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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