Defining the function of tubulin post-translational modifications in female meiosis
NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development
About This Grant
PROJECT SUMMARY Female meiosis generates fertilizable eggs from progenitor oocytes. Chromosome segregation in oocytes is driven by a microtubule-based spindle machinery. For poorly understood reasons, oocytes are highly predisposed to chromosome segregation errors that lead to aneuploidies, with these chromosomal abnormalities accounting for up to 35% of miscarriages. Oocyte aneuploidy rates increase dramatically with advancing maternal age, which severely impacts pregnancy outcomes. This proposal will investigate microtubule organization and chromosome segregation mechanisms in oocytes and probe the molecular origins of egg aneuploidy. The microtubule cytoskeleton is built from tubulin heterodimers that are subject to various post- translational modifications (PTMs). Tubulin PTMs are postulated to control microtubule diversity and function in many cell types. However, their role in oocyte meiosis and whether tubulin PTM dysfunction underlies high chromosome segregation error rates in female meiosis is unknown. In this research, I will use mouse oocytes, a well-established model of mammalian oocyte meiosis, to address this fundamental conceptual gap in reproductive biology. I will achieve this by pursuing two specific aims. In Aim 1, I will define the tubulin PTM profile of oocytes using quantitative immunofluorescence microscopy and western blotting analyses. To study tubulin PTM function in oocytes, I will disrupt PTMs using innovative rapid protein degradation tools. By combining this approach with high-resolution and super-resolution live and immunofluorescence microscopy of microtubules, chromosomes, and cytoskeletal proteins, I will identify tubulin PTMs that are required for organization and dynamics of cytoplasmic microtubules, meiotic spindle assembly, and chromosome segregation. In further mechanistic experiments, I will probe how tubulin PTM disruption impacts microtubule- associated proteins that drive microtubule organization and chromosome segregation. In Aim 2, I will investigate how tubulin PTM dysfunction contributes to age-related oocyte aneuploidy. Recent work from our lab and others revealed that cytoskeletal dysfunction contributes to age-related aneuploidy. I will examine whether dysregulated microtubule modification underlies cytoskeletal dysfunction at advanced reproductive ages by taking a candidate-based approach to identify tubulin modifying enzymes that are altered in aged oocytes. By combining experimental approaches from Aim 1 with enzyme overexpression approaches, I will override microtubule modifications and ask whether dysregulation of identified PTM candidates is sufficient to induce aging-like chromosomal phenotypes in young oocytes. Conversely, I will test whether targeted manipulation of tubulin PTMs can rescue chromosome segregation fidelity in aged oocytes. Integrated approaches from these two aims are likely to reveal key post-translational modifications of tubulin proteins that govern oocyte-specific cytoskeletal structures and chromosome segregation mechanisms. Uncovering new root causes of high aneuploidy rates in this research could accelerate new therapeutics against human infertility and genetic disorders.
Grant Summary
Defining the function of tubulin post-translational modifications in female meiosis is a NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development grant providing up to $50K for university, nonprofit, healthcare org. Applications are due 2029-06-30 (open). Check eligibility and apply with FindGrants.
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Up to $50K
2029-06-30
- 1Confirm your organization is eligible for Defining the function of tubulin post-translational modifications in female meiosis 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.
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Defining the function of tubulin post-translational modifications in female meiosis: Frequently Asked Questions
Who is eligible for the Defining the function of tubulin post-translational modifications in female meiosis?
Defining the function of tubulin post-translational modifications in female meiosis 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 Defining the function of tubulin post-translational modifications in female meiosis provide?
Defining the function of tubulin post-translational modifications in female meiosis provides up to $50K 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 Defining the function of tubulin post-translational modifications in female meiosis deadline?
Applications for Defining the function of tubulin post-translational modifications in female meiosis are due 2029-06-30 (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 Defining the function of tubulin post-translational modifications in female meiosis?
To apply for Defining the function of tubulin post-translational modifications in female meiosis, 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.