Mitochondrial factories for AMD therapy
About This Grant
PROJECT SUMMARY Age-related macular degeneration (AMD) is the leading cause of irreversible blindness involving gradual dysfunction and degeneration of photoreceptors and the retinal pigment epithelium (RPE). Mitochondrial dysfunction represents a hallmark of AMD. Excessive and persistent reactive oxygen species (ROS) damages mitochondrial DNA (mtDNA), resulting in fewer mitochondria. Impairments in respiratory chain activity and reduced oxidative phosphorylation (OXPHOS) impacts ATP synthesis and further drives ROS production. Our prior work has shown that exogenous mitochondrial transplantation to cells can induce a bioenergetic shift towards increased OXPHOS and ATP production, and reduced ROS. Mitochondrial cell-to-cell transfer in response to stress rescues aerobic respiration to reduce deleterious cell dynamics. We aim to create a sustainable source of mitochondria proximal to the RPE in the form of mesenchymal stem cells (MSCs) transfected with nuclear respiratory factor 1 (NRF1), a driver of mitochondrial biogenesis, for enhanced cell-to- cell transfer of mitochondria. Our objectives are to determine how NRF1 transfection changes MSC transcriptional activity, mitochondrial production and trafficking, and extracellular vesicle (EV) contents, and test the strategy in two rodent models of retinal degeneration. We hypothesize that our cell therapy using NRF1- overexpressing MSCs will not only provide the needed energetic boost via mitochondrial mass transfer to retinal cells, but also induce profound cellular reprogramming through the secretion of EV-containing factors, thereby counteracting and potentially reversing the onset of late-stage dry AMD. We will use a combination of molecular and biochemical methods, including transcriptomics, to characterize the potency of mitochondrial transfer to impact AMD. We will first investigate the impact of NRF1 on mitochondrial transfer mechanisms in MSCs. We will elucidate the role of NRF1 on mitochondrial transfer mechanisms, specifically tunneling nanotubes (TNTs) and EVs, between MSCs and human RPE cells from donor eyes afflicted with AMD, shedding light on NRF1- primed MSCs as mitochondria generators, responsive to signals from stressed cells. We will then examine the influence of NRF1 on MSC senescence and EV composition, providing insights into the multifaceted benefits of NRF1 in MSCs, including metabolic adaptation to AMD stress environments and modulation of EV constituents. Lastly, we will evaluate the impact of NRF1 primed MSC transplantation in vivo. Through longitudinal and long- term efficacy studies and tissue transcriptomic analysis, we will identify disease stages most responsive to NRF1 MSCs when transplanted subretinally in a sodium iodate (NaIO3)-induced model of retinal degeneration and senescence accelerated mouse (SAMP8) model, highlighting the potential to rescue RPE cell degeneration and abrogate AMD progression. Findings from this work will provide crucial insights into the potential of NRF1-based therapies for AMD, offering a promising avenue for the treatment and management of this debilitating disease.
Grant Summary
Mitochondrial factories for AMD therapy is a NEI - National Eye Institute grant providing up to $1.0M for university, nonprofit, healthcare org. Applications are due 2028-04-30 (open). Check eligibility and apply with FindGrants.
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How to Apply
Up to $1.0M
2028-04-30
- 1Confirm your organization is eligible for Mitochondrial factories for AMD therapy from NEI - National Eye 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 NEI - National Eye Institute before the deadline.
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Mitochondrial factories for AMD therapy: Frequently Asked Questions
Who is eligible for the Mitochondrial factories for AMD therapy?
Mitochondrial factories for AMD therapy 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 Mitochondrial factories for AMD therapy provide?
Mitochondrial factories for AMD therapy provides up to $1.0M 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 Mitochondrial factories for AMD therapy deadline?
Applications for Mitochondrial factories for AMD therapy 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 Mitochondrial factories for AMD therapy?
To apply for Mitochondrial factories for AMD therapy, 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.