Using State-of-the-Art Technologies and Murine Models for Novel cGVHD Therapies
NHLBI - National Heart Lung and Blood Institute
About This Grant
Our primary goal is to acquire new insights into chronic GVHD (cGVHD) pathobiology to create new therapies to limit fibrosis. We’ve shown that T:B cell engagement can initiate cGVHD by causing pathogenic αhost immunoglobulin (Ig) deposition that exacerbates tissue injury, recruits monocytes (monos) and TGFβ-secreting macrophage (Macs), and stimulates fibroblast/myofibroblast/endothelial cell pro-fibrinogenic cytokines. Our central hypothesis is that developing effective αfibrotic therapies requires greater elucidation of tissue cellular mechanisms and dynamic evolution processes that culminate in cGVHD. We will use state-of-the-art techniques in valid mouse models to expose cGVHD vulnerabilities. Tissues will be obtained at an early and late timepoint from cGVHD mice with bronchiolitis obliterans (BO) or scleroderma (Scl) to assess cGVHD progression in lymphoid and cGVHD organs. In an innovative, scientifically and technologically unprecedented, approach we will interrogate cGVHD mechanisms in BO and Scl models by spatially and temporally resolving and integrating proteomics with whole genome transcriptomics at a single cell resolution within histopathological regions of interest. This will result in a spatiotemporal atlas mapping how specific cells drive cGVHD disease progression in both lymphoid and target tissues; an invaluable tool for future studies. Our specific aims will test the hypotheses that: Aim 1. Interrogating T cell:B cell crosstalk at cGVHD tissue sites will lead to novel therapeutics and individualized applications. During the mechanistic discovery phase, we will infuse bifunctional (suppressive and cytolytic) αCD19 scFv chimeric antigen receptor (CAR19) Tregs to preclude B cell support of pathogenic IgG secretion, leveraging our murine cGVHD/BO cell atlas to assess the means by which these cells disrupt cGVHD progression. Aim 2. cGVHD tissue injury recruits monos that evolve into αinflammatory, pro-fibrinogenic Macs and engagement with fibroblasts/myofibroblasts to initiate fibrosis. Coupling mono and Mac reporter and deleter donor mice with spatiotemporal multi-omics, we will define the mechanisms by which monos and Macs enter cGVHD tissues and pro-fibrotic cytokines are produced, leading to new and key therapeutic targets. To halt fibrosis, mannosylated lipid nanoparticles with TGFβ1 siRNA will be given to selectively bind CD206+ Macs linked to murine cGVHD/BO and Scl. Aim 3. Mac communication with fibroblasts/myofibroblasts causes fibrosis that can be halted by fibroblast activation protein (FAP) CAR Tregs. Utilizing our first of its kind cell atlas of disease progression, we will elucidate the nature of crosstalk between profibrogenic TGFβ-producing Macs, fibroblasts, myofibroblasts and endothelial cells culminating in tissue fibrosis. We show FAP upregulation in cGVHD lung (BO), skin (Scl) and cGVHD/Scl patients and will infuse FAP CAR Tregs to eliminate damaged cells. We will fill cGVHD pathophysiology knowledge gaps for mechanistic insights focused on T:B and Mac: fibroblast/myofibroblast/endothelial cell (fibrosis) crosstalk, test novel therapies in clinically relevant models and, with mature data, assist Dr. Pavletic to lead cGVHD CAR trials at the NIH Clinical Center using intramural funds
Grant Summary
Using State-of-the-Art Technologies and Murine Models for Novel cGVHD Therapies is a NHLBI - National Heart Lung and Blood Institute grant providing up to $1.6M for university, nonprofit, healthcare org. Applications are due 2028-02-29 (open). Check eligibility and apply with FindGrants.
Focus Areas
Eligibility
How to Apply
Up to $1.6M
2028-02-29
- 1Confirm your organization is eligible for Using State-of-the-Art Technologies and Murine Models for Novel cGVHD Therapies from NHLBI - National Heart Lung and Blood Institute, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
- 4Review every section against the requirements checklist, then export a submission-ready application pack and submit it to NHLBI - National Heart Lung and Blood Institute before the deadline.
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Using State-of-the-Art Technologies and Murine Models for Novel cGVHD Therapies: Frequently Asked Questions
Who is eligible for the Using State-of-the-Art Technologies and Murine Models for Novel cGVHD Therapies?
Using State-of-the-Art Technologies and Murine Models for Novel cGVHD Therapies is offered by NHLBI - National Heart Lung and Blood Institute and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Using State-of-the-Art Technologies and Murine Models for Novel cGVHD Therapies provide?
Using State-of-the-Art Technologies and Murine Models for Novel cGVHD Therapies provides up to $1.6M per award from NHLBI - National Heart Lung and Blood Institute. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Using State-of-the-Art Technologies and Murine Models for Novel cGVHD Therapies deadline?
Applications for Using State-of-the-Art Technologies and Murine Models for Novel cGVHD Therapies are due 2028-02-29 (open). Because deadlines can change, verify the date with the funder, NHLBI - National Heart Lung and Blood Institute, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Using State-of-the-Art Technologies and Murine Models for Novel cGVHD Therapies?
To apply for Using State-of-the-Art Technologies and Murine Models for Novel cGVHD Therapies, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NHLBI - National Heart Lung and Blood Institute.