Interrogating microglia-driven retinal ganglion cell and vascular dysfunction in metabolic syndrome associated retinopathy
NEI - National Eye Institute
About This Grant
PROJECT SUMMARY Retinal vascular diseases including diabetic retinopathy (DR) are a leading cause of vision loss worldwide. Current DR treatments center on reducing retinal vascular dysfunction and neovascularization. These treatments do not improve all outcomes and can reduce visual acuity underscoring the need for novel therapeutics targeting additional aspects of DR. Early neural deficits including retinal ganglion cell loss (RGC) have been identified in both patients and in DR mouse models. Microglia have been implicated in retinal neurodegenerative conditions including DR. Recent work indicates microglial mitochondrial function and metabolic flexibility drives dysfunctional responses. Yet, while human DR is linked to metabolic and mitochondrial stress how this perturbs microglia and if this drives RGC loss and microvascular damage is not clear. The goal of this project is to identify and test mechanisms by which microglia influence RGC and retinal vascular health in a DR-relevant context. Our recent work identified NZO mice (a polygenic model of metabolic syndrome) as a novel model of DR-relevant metabolic syndrome associated retinopathy. NZO mice develop hallmarks of human DR including cotton wool spots, exudates, and capillary loss. In particular, NZO mice develop microvascular dysfunction concomitant with neural deficits (initiates by 3mo) and significant RGC dysfunction and loss by 12mo. Preliminary data from single nucleus and single cell RNA-seq experiments comparing NZO (retinopathy) and B6J mice (control) suggested microglia differentially influence RGCs in B6J compared to NZO retinas. Further, NZO microglia exhibited age- dependent changes in diabetic wound healing genes, and lower expression of metabolic genes compared to B6J microglia suggesting metabolic dysregulation may underlie abnormal microglia-RGC communication. Therefore, in Aim 1, I will identify mechanisms by which microglia influence RGCs and the vascular cells using single cell RNA-seq, microglia depletion, and data alignment strategies. Additional preliminary analyses of our mouse datasets and available patient data indicate lower expression of nicotinamide metabolic enzymes in RGCs and microglia reinforcing the possibility that metabolic dysfunction may contribute to retinopathy- progression. Thus, in Aim 2 I will examine the therapeutic potential of improving cellular metabolism in NZO mice through nicotinamide and pyruvate supplementation or by increasing expression of nicotinamide mononucleotide adenylyl transferases in RGCs and microglia via AAVs. In Aim 3, in a candidate target approach I will first determine the impact of advanced glycation end products signaling in microglia on DR progression. I will then take an unbiased candidate prioritization approach and utilize data generated in Aim 1 to identify and test additional human-relevant processes that may drive pathology. Through these Aims, I will acquire essential skills to facilitate my transition to an independent investigator studying the role of microglia in retinal disease. This project will be supported by a mentoring committee of globally recognized experts in retinal neurodegeneration, microglia, and bioinformatics and excellent career development resources.
Grant Summary
Interrogating microglia-driven retinal ganglion cell and vascular dysfunction in metabolic syndrome associated retinopathy is a NEI - National Eye Institute grant providing up to $140K for university, nonprofit, healthcare org. Applications are due 2028-04-30 (open). Check eligibility and apply with FindGrants.
Focus Areas
Eligibility
How to Apply
Up to $140K
2028-04-30
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- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
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Interrogating microglia-driven retinal ganglion cell and vascular dysfunction in metabolic syndrome associated retinopathy: Frequently Asked Questions
Who is eligible for the Interrogating microglia-driven retinal ganglion cell and vascular dysfunction in metabolic syndrome associated retinopathy?
Interrogating microglia-driven retinal ganglion cell and vascular dysfunction in metabolic syndrome associated retinopathy is offered by NEI - National Eye 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 Interrogating microglia-driven retinal ganglion cell and vascular dysfunction in metabolic syndrome associated retinopathy provide?
Interrogating microglia-driven retinal ganglion cell and vascular dysfunction in metabolic syndrome associated retinopathy provides up to $140K per award from NEI - National Eye 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 Interrogating microglia-driven retinal ganglion cell and vascular dysfunction in metabolic syndrome associated retinopathy deadline?
Applications for Interrogating microglia-driven retinal ganglion cell and vascular dysfunction in metabolic syndrome associated retinopathy are due 2028-04-30 (open). Because deadlines can change, verify the date with the funder, NEI - National Eye Institute, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Interrogating microglia-driven retinal ganglion cell and vascular dysfunction in metabolic syndrome associated retinopathy?
To apply for Interrogating microglia-driven retinal ganglion cell and vascular dysfunction in metabolic syndrome associated retinopathy, 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 NEI - National Eye Institute.