Transcriptional and developmental basis of the human x-linked homeotic hotspot

Ended Project Grant Awarded Last action

Award ID
F31EY036742
Recipient
Awarding agency
Obligated
$168,452

Award facts

Assistance listing
93.867 Vision Research
Completion date
Place of performance
Davis, CA, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Human eye development is an exquisitely balanced crosstalk of numerous signaling pathways that iteratively dictate the EBB and flow of this complex and highly physiologically active organ. Amongst the plethora of genetic mutations that can derail this sensitive programming, larger scale ocular malformations are encapsulated under a spectrum known as microphthalmia (small eye globes), anophthalmia (missing eye globes), and coloboma (failed closure of the choroid fissure), collectively referred as MAC syndrome that affects approximately 1:10,000 live births. The following proposal highlights an anomalous index case of human bilateral anophthalmia and XX SEX-reversal (basr) syndrome. This anatomically male child was born with bilateral anophthalmia, a left cystic orbital mass, focal brain lesions, and is genetically female (XX). Their disease is the result of a DE novo mutation on the long arm of their paternal x chromosome (XQ27). This region contains an extra copy of a large fragment (640K base pairs) from the long arm of chromosome 9 (9Q21) which translocated during paternal meiosis i. The translocated fragment contained regulatory elements of an ION channel gene, TRPM3. Most fascinatingly, the exact point in which the translocation happened was at a 180 base pair palindrome on XQ27 that has been the causal site of mutation for a staggering number of other congenital disorders that affect, not just the eye, but numerous other tissue compartments or organ systems. These disorders involve the translocation of different autosomal fragments that land at this locus. To address basr etiology, as well as molecularly unify all the disorders that map back to this translocation hotspot, we hypothesize that SOX3, a neighboring transcription factor, is ectopically activated within tissue domains that correspond to the translocated fragments. Additionally, we hypothesize that SOX3 in basr was activated in the pigmented monolayer of cells in the back of the retina (retinal pigment epithelium; RPE) that is essential for photoreceptor health and ocular genesis. The following training plan seeks to test this hypothesized SOX3 etiology through both in vitro and in vivo modalities. By utilizing immortalized blood cells from the basr patient, i aim to characterize the misfolded higher-order genetic landscape that comprises the XQ27 mutation through sequencing of closely associated regions (HI-c). Additionally, induced pluripotent stem cells from the basr patient will be induced to become RPE, during which i will gather and conduct serial analysis of the genetic expression of this process within a basr context via single-cell sequencing. I aim to complement these efforts with characterization of a basr mouse model, in which partially formed eye rudiments within these newly generated transgenic mice that ectopically express SOX3 will be immuno-detected and qualitatively assessed for any potential transdifferentiation.

Transactions

Action Obligated Date
Amendment $42,536
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Amendment $41,972
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Original award $41,972
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Quick answers

Who received award F31EY036742?

F31EY036742 was awarded to University Of California, Davis by National Eye Institute (National Institutes of Health) on March 1, 2025.

How much is award F31EY036742 worth?

$168,452 has been obligated on F31EY036742.

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