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Unravelling the molecular complexity behind ocular maldevelopment (360G-Wellcome-205174_Z_16_Z)

<p><strong>Aim:</strong> Investigating the relationship between genotype, gene expression and phenotype of <u>m</u>icrophthalmia, <u>a</u>nophthalmia&nbsp;and ocular <u>c</u>oloboma&nbsp;(MAC), which collectively causes one-third of life-long blindness and severe visual impairment in children worldwide.</p> <p>&nbsp;</p> <p><strong>Research questions: </strong>What are the pathogenic variants underlying MAC? How do molecular subtypes correlate with phenotype and stratify clinical risk?&nbsp; What molecular pathways are involved in human eye development? What is the relationship between genotype and gene expression in microphthalmia?</p> <p>&nbsp;</p> <p><strong>Key goals and methodology:</strong></p> <ol> <li>Whole genome sequencing of 30 parent-offspring trios with isolated MAC and longitudinal phenotyping. Establish an international reference network to stratify a well-defined cohort to improve care pathways and future research.</li> <li>Temporal comparative analysis of DNA methylome (bisulfite conversion and Illumina Infinium EPIC BeadChips) and transcriptome (65 million reads per sample using Illumina HiSeq-2500) in the developing human eye between 4-9 weeks gestation.</li> <li>Model 3D human microphthalmic optic cups using iPSC technology with isogenic controls using CRISPR/Cas9 gene-editing. DNA methylome and transcriptome analysis to assess disruption of molecular pathways.</li> </ol> <p>&nbsp;</p> <p><strong>Outcomes:</strong> Establish a molecular framework for ocular maldevelopment. Identify drug targets and develop therapeutics. Improve genetic diagnosis, counselling and management. Elucidate shared molecular mechanisms between embryonic tissue fusion defects and late-onset visual sensory disorders.&nbsp;</p>


06 Dec 2016

Grant details
Amount Awarded 1133875
Applicant Surname Moosajee
Approval Committee Clinical Interview Committee
Award Date 2016-12-06T00:00:00+00:00
Financial Year 2016/17
Grant Programme: Title Clinical Research Career Development Fellowship
Internal ID 205174/Z/16/Z
Lead Applicant Dr Mariya Moosajee
Planned Dates: End Date 2022-04-01T00:00:00+00:00
Planned Dates: Start Date 2017-04-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Greater London
Sponsor(s) Prof Philip Luthert
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