Lymphatic primary cilia regulation of intercellular junctions and valve formation
NHLBI - National Heart Lung and Blood Institute
About This Grant
Lymphatic valve dysfunction disrupts lymph transport, causing lymphedema – a condition characterized by irreversible tissue fibrosis and increased infection risk due to impaired immunosurveillance. Current standard of care manual lymph drainage and compression therapy fail to target the underlying molecular defects. This NIH R01 proposal builds on our discovery of the intraflagellar transport (IFT) system in lymphatic endothelial cells (LECs), focusing on IFT74 and IFT20 as critical regulators of lymphatic valve morphogenesis. IFT proteins, such as IFT74, are required for the assembly and maintenance of primary cilia, cell surface chemo- /mechanosignaling organelles that we recently discovered on LECs. IFT20 also performs essential non-ciliary processes, including trafficking adhesion and extracellular matrix (ECM) proteins. Our central hypothesis is that IFT proteins assemble primary cilia to promote shear stress-dependent lymphatic valve initiation and support valve maturation by non-ciliary trafficking of ECM and adhesion proteins to the cell surface to reinforce valve leaflets. Our preliminary data reveal that LEC-specific IFT74 knockout (KO) mice suffer defects in valve formation, while IFT20 KO mice show excessive lymphangiogenesis and impaired VE-cadherin recycling with more modest valve maturation defects, highlighting their distinct contributions. Specific Aim 1 will determine how IFT74/primary cilia enable lymphatic endothelial cells (LECs) to sense shear stress and initiate valve development. We will investigate ciliary signaling pathways using in vitro calcium flux assays, the role of transcriptional de-repression in valve morphogenesis, and identify valve-specific gene networks controlled by primary cilia via spatial transcriptomics. Specific Aim 2 will investigate how non-ciliary IFT20 regulates valve maturation by coordinating VE-cadherin recycling, integrin adhesion, and ECM deposition to stabilize valve leaflets. To determine how non-ciliary IFT20 exocytic trafficking promotes valve maturation, we will use intravital microscopy with transgenic reporters and second harmonic generation to observe valve formation and junctional/ECM dynamics in real time. We aim to elucidate the mechanisms of valve initiation and maturation, positioning IFT74/primary cilia and IFT20 and their downstream effectors as potential therapeutic targets for lymphedema. By connecting ciliary mechanosensation to valve development and non-ciliary trafficking to valve stability, we will build a comprehensive molecular model of IFT regulation of valve morphogenesis. Aligned with the NIH NOSI on the lymphatic system, this research seeks to enhance lymphatic transport capacity and guide the development of new therapies for lymphatic disorders.
Grant Summary
Lymphatic primary cilia regulation of intercellular junctions and valve formation is a NHLBI - National Heart Lung and Blood Institute grant providing up to $453K for university, nonprofit, healthcare org. Applications are due 2031-01-31 (open). Check eligibility and apply with FindGrants.
Focus Areas
Eligibility
How to Apply
Up to $453K
2031-01-31
- 1Confirm your organization is eligible for Lymphatic primary cilia regulation of intercellular junctions and valve formation 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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Lymphatic primary cilia regulation of intercellular junctions and valve formation: Frequently Asked Questions
Who is eligible for the Lymphatic primary cilia regulation of intercellular junctions and valve formation?
Lymphatic primary cilia regulation of intercellular junctions and valve formation 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 Lymphatic primary cilia regulation of intercellular junctions and valve formation provide?
Lymphatic primary cilia regulation of intercellular junctions and valve formation provides up to $453K 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 Lymphatic primary cilia regulation of intercellular junctions and valve formation deadline?
Applications for Lymphatic primary cilia regulation of intercellular junctions and valve formation are due 2031-01-31 (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 Lymphatic primary cilia regulation of intercellular junctions and valve formation?
To apply for Lymphatic primary cilia regulation of intercellular junctions and valve formation, 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.