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Novel therapeutic and spatial proteomics approaches to determine macrophage-fibroblast cross-talk during chronic GVHD

Award Number: F32HL186726
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/06/2027
PERIOD OF PERFORMANCE END DATE: 01/05/2028

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Novel therapeutic and spatial proteomics approaches to determine macrophage-fibroblast cross-talk during chronic GVHD - ABSTRACT Chronic graft-versus-host disease (cGVHD), a debilitating complication of allogeneic hematopoietic stem cell transplantation, is characterized by immune dysregulation, autoimmunity, and/or fibrosis. Our lab has shown that T:B cell cooperativity produces host immunoglobulin deposited in cGVHD tissues, triggering monocytes (monos) and macrophages (macs) recruitment and pro-fibrinogenic cytokine secretion by fibroblasts/myo- fibroblasts resulting in fibrosis. Particularly devastating are a fibrotic lung airway obstructive disease (bronchiolitis obliterans, BO) and scleroderma-like (Scl) skin fibrosis. The Blazar lab has developed the only bona fide preclinical model of BO and multiple models of Scl to investigate disease pathology and develop new therapeutic strategies to treat cGVHD. Our preclinical models have provided key foundational data toward the 4 FDA approved therapies, including axatilimab (CSF1R mAb), the first drug to target macs in cGVHD. Profibrotic macs are anti-inflammatory and secrete TGF that is required for normal tissue repair but also can induce fibrosis. In cGVHD patients, despite effective peripheral mac depletion by axatilimab, complete responses are rare and patients with partial responses have a high incidence of infections, amongst other comorbidities, highlighting an unmet need for more targeted therapies. Aim1 will determine the distinct cellular landscape of monos/macs in BO and Scl target tissues. I will employ high dimensional (spectral) flow cytometry, I will identify and track mac subsets and discern the sequence and kinetics of transition of circulating donor mono into lung (BO) or skin (Scl) tissue resident macs (aim 1A). Using CellScape, a spatial proteomics platform, I will quantify the juxtaposition between tissue resident macs from dual reporter donor mice to host extracellular matrix producing fibroblasts and myofibroblasts. To determine whether tissue resident macs are critical to cGVHD pathobiology, I will leverage CX3CR1-DTR mice in our lab to temporally delete CX3CR1+ macs that become tissue resident macs and determine how cGVHD pathophysiology is altered (aim 1B). In aim 2, I will determine the differential effects of mac depletion by CSF-1R mAb to functional inhibition of CD206+ mac by MANP/TGF1 siRNA on cGVHD outcomes (aim 2A) and protective immunity to an intratracheal, nonlethal dose of an endemic influenza A virus strain (aim 2B). The proposed studies will provide valuable insight into the disease mechanisms in distinct models of fibrotic cGVHD and determine the tissue-specific benefits of mac depletion compared to selective CD206+ mac TGF silencing on protective viral immunity in untreated or mac targeted mice with GVHD immunosuppression. This project will allow me to enhance my knowledge in murine cGVHD immunobiology, lung anti-viral responses and mono/mac differentiation, tissue migration and function. New technical skills will include synthesis of siRNA containing nanoparticle and acquiring spatial proteomics data and training in bioinformatic analytics. Upon completing the proposed F32 experiments and in-depth training, I will be better positioned to achieve my goal in becoming a transplantation immunologist in academia.


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 = $79,348 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Blood Diseases and Resources Research	000	1	7/7/2026	NEW	$79,348
														Subtotal = $79,348

Grand Total All Awards = $79,348

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Novel therapeutic and spatial proteomics approaches to determine macrophage-fibroblast cross-talk during chronic GVHD

Award Number: F32HL186726

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/06/2027

PERIOD OF PERFORMANCE END DATE: 01/05/2028

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