Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY The developing embryo has the remarkable ability to buffer insults, ensuring normal development in the face of genetic and environmental influences. But when these insults exceed a disease threshold - birth defects can result. Our goal is to elucidate how these buffering systems mediate the interplay between genes and environment and if disruption of these buffering systems contributes to structural birth defects in genetic syndromes. Resistance to perturbations is known as developmental robustness, and miRNA-mediated negative feedback loops potentially play critical roles in buffering genetic and environmental insults. Disruption of miRNAs results in increased sensitivity to environmental factors in model organisms; yet, whether the miRNA-mediated buffering mechanisms play a role in birth defects remains unknown. This proposal will investigate whether defective miRNA-mediated buffering drives the phenotypic variability in 22q11.2 deletion syndrome (22q11DS). 22q11DS is the most common deletion syndrome in humans, with variable features independent of the size of the deletion. It is well accepted that variability is due to the influence of genetic and environmental modifiers, but the identity of these factors still needs to be discovered. Preliminary data indicate that mouse models of 22q11DS exhibit abnormal vitamin A/Retinoic acid signaling regulation, and dietary supplementation of the maternal diet with vitamin A (within recommended levels for pregnancy) is a modifier of outflow tract (OFT) defects in a mouse model of 22q11DS. Furthermore, Dgcr8 is deleted in 22q11DS. Due to its essential role in synthesizing mature miRNAs, Dgcr8 is an exciting but unexplored candidate for mediating abnormal buffering of signal transduction pathways in 22q11DS. This proposal aims to test the hypothesis that maternal dietary intake of vitamin A is an important modifier of OFT defects in 22q11DS, potentiated by the altered capacity of the 22q11DS embryo to buffer changes in vitamin A intake. We propose that reduced buffering capacity transforms benign vitamin A exposures into teratogenic doses by failing to rapidly engage miRNA-mediated negative feedback mechanisms to buffer retinoic acid signaling. Moreover, Tbx1 is deleted in 22q11DS and implicated in congenital heart defects (CHDs) in 22q11DS. However, the haploinsufficiency of Tbx1 results in low penetrance of OFT defects. We propose that altered buffering capacity in 22q11DS amplifies RA signaling and reduces Tbx1 gene dosage below a threshold needed for proper OFT development. This novel mechanism for aberrant gene-environment interactions will be tested with two specific aims: To establish (1) how RA buffering is disrupted in 22q11DS; and (2) if reduced miRNA processing due to Dgcr8 haploinsufficiency mediates altered RA buffering and contributes to OFT defects in 22q11DS. Together, these experiments will provide a novel understanding of the mechanisms mediating gene-environment interactions. This new insight can directly translate to preventing structural birth defects in 22q11DS.
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