Control of Developmental Timing by NADH Redox Metabolism
NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development
About This Grant
PROJECT SUMMARY Proper embryonic development requires the precise orchestration of a series of well-conserved developmental steps in both space and time. Defects in the temporal unfolding of these steps can give rise to congenital diseases. Surprisingly, the speed of embryonic development is highly species-specific. For instance, among mammals, the duration of embryogenesis ranges from 15 days in mice to 116 days in elephants. Understanding how these species-specific developmental rates are set could have significant translational potential, including accelerating stem cell differentiation for cell therapies or decelerating cellular processes to combat tumor growth and aging. To precisely measure developmental speed across species, we rely on the segmentation clock, a molecular oscillator whose period tightly correlates with the duration of embryogenesis. We have recapitulated the segmentation clock in vitro using mouse and human pluripotent stem cells, therefore enabling cross-species comparisons. Using this experimental platform, we recently found that a key factor regulating developmental speed is the cytosolic NAD+/NADH ratio. This parameter was elevated in mouse cells (fast-developing) compared to human cells (slow-developing). Moreover, experimentally lowering the NAD+/NADH ratio slowed down the segmentation clock, whereas its increase resulted in acceleration. Here we propose to identify the mechanisms that give rise to differential cytosolic NAD+/NADH ratios between species. Cytosolic redox balance is known to be regulated by NADH shuttling systems that oxidize NADH in the cytosol and transfer the reducing equivalents to the mitochondria. Two primary NADH shuttles exist: the glycerol-3-phosphate (G3P) and the malate-aspartate (MA) shuttle. Preliminary data suggest that the G3P shuttle is more active in mouse embryonic cells than in human cells due to differential expression of shuttle enzymes. We hypothesize that species-specific expression of G3P shuttle components in mouse and human embryonic cells drives differences in G3P shuttle activity, thereby establishing distinct cytosolic NAD+/NADH ratios and contributing to the disparity in developmental speed between these two species. In Aim 1, we will directly test the role of NADH shuttles in establishing species-specific NAD+/NADH ratios by comparing shuttle fluxes between mouse and human embryonic cell types, and by manipulating the expression of shuttle components. In Aim 2, we will investigate the regulatory mechanisms underlying species-specific expression of NADH shuttle components, particularly GPD1L, a key enzyme in the G3P shuttle which is expressed in mouse cells but not human cells. By identifying the cis- and trans-regulatory elements controlling species-specific GPD1L expression, we will begin to uncover the genetic basis for differences in developmental speed between species. Overall, the proposed research will provide critical insights into species-specific developmental timing and enhance the utility of human stem cells for therapeutic applications by devising novel strategies for the acceleration of developmental rate.
Grant Summary
Control of Developmental Timing by NADH Redox Metabolism is a NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development grant providing up to $538K for university, nonprofit, healthcare org. Applications are due 2031-04-30 (open). Check eligibility and apply with FindGrants.
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Up to $538K
2031-04-30
- 1Confirm your organization is eligible for Control of Developmental Timing by NADH Redox Metabolism from NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development, 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.
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Control of Developmental Timing by NADH Redox Metabolism: Frequently Asked Questions
Who is eligible for the Control of Developmental Timing by NADH Redox Metabolism?
Control of Developmental Timing by NADH Redox Metabolism is offered by NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development 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 Control of Developmental Timing by NADH Redox Metabolism provide?
Control of Developmental Timing by NADH Redox Metabolism provides up to $538K per award from NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development. 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 Control of Developmental Timing by NADH Redox Metabolism deadline?
Applications for Control of Developmental Timing by NADH Redox Metabolism are due 2031-04-30 (open). Because deadlines can change, verify the date with the funder, NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Control of Developmental Timing by NADH Redox Metabolism?
To apply for Control of Developmental Timing by NADH Redox Metabolism, 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 NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development.