Browsing by Author "Patel, Rushiv"

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    Effects of the Calcineurin/NFAT Pathway in Skeletal Abnormalities Associated with Down Syndrome
    (Office of the Vice Chancellor for Research, 2015-04-17) Thomas, Jared; Patel, Rushiv; Roper, Randall J.
    Down Syndrome (DS) is a genetic disorder caused by trisomy of human chromosome 21 (Hsa21). DS phenotypes include cognitive impairment, craniofacial abnormalities, and skeletal deficiencies. The Ts65Dn mouse model exhibits similar phenotypes as found in humans with DS, including deficits in skeletal bone. Over-expression of DYRK1A, a serine-threonine kinase encoded on Hsa21, has been linked to deficiencies in DS bone homeostasis. Calcineruin/NFAT pathway plays a role in bone homeostasis by regulating osteoblastogenesis and osteoclastogenesis. DYRK1A was found to regulate calcineruin/NFAT signaling to block transcriptional activity, thereby reducing calcineruin/NFAT transcriptional activity. Epigallocatechin-3-gallate (EGCG), an aromatic polyphenol found in green tea, is a known inhibitor of DYRK1A activity. Normalization of DYRK1A activity by EGCG may have the potential to regulate bone homeostasis, by increasing bone mineral density (BMD) and bone strength. In earlier our work, EGCG treatment of 30mg/kg/day, has been shown to improve skeletal deficits, however, the mechanism remains unknown. We hypothesize that EGCG is involved in the calcineurin/NFAT pathway. To test our hypothesis we will use cyclosporine A (CsA), an immunosuppressant that perturbs the calcineurin/NFAT pathway. Previous studies show that daily administration of high concentration CsA will result in significant bone loss. Three-week old euploid and trisomic Ts65Dn mice receive 30mg/kg/day of CsA or vehicle for 3 weeks. In addition, mice will receive EGCG or water. At six weeks of age, BMD, bone strength, as well as architecture of the cortical and trabecular bone are assessed in extracted femurs. We expect that CsA given to euploid mice exhibit bone phenotypes similar to trisomic mice. Whereas euploid mice given CsA and EGCG might display bone phenotypes similar to euploid given only the vehicle. Provided that we are able to observe our expected results, it may indicate that EGCG is involved in the calcineurin/NFAT pathway. Our work is important to understand how EGCG may affect DS phenotypes as the EGCG is translated to human use.
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    Genomic Analysis of Gene Dysregulation Sites Related to Craniofacial Development in Ts65Dn Down Syndrome Mouse Embryos
    (Office of the Vice Chancellor for Research, 2015-04-17) Patel, Rushiv; Roper, Randall J.
    Down syndrome (DS) is caused by a nondisjunction event called Trisomy 21 and is known to effect every system of the body. While it is thought that select genes on chromosome 21 are responsible for specific DS phenotypes, we are unsure of the overall effect the extra genetic information poses across the genome. The presence of an extra chromosome 21 is suspected to cause dysregulation in gene expression across the genome of individuals with DS. These dysregulation sites may vary between individuals due to genetic variability and according to tissue type. Previous studies have shown that genomic regions of gene up regulation and down regulation exist in individuals with DS. Ts65Dn mice have an extra marker chromosome that accounts for approximately fifty percent of the genes that are triplicated in DS. We are using the Ts65Dn DS mouse model to study the variability in the genomic sites of dysregulation caused by trisomy and to determine whether genomic dysregulation is tissue specific. We are comparing the gene expression from genes associated with the neural tube and 1st pharyngeal arch from trisomic and euploid e9.5 embryos. This comparison may provide insight behind the effect trisomy has on genomic dysregulation that causes the small 1st pharyngeal arch and leads to a small mandible in individuals with DS. Significantly dysregulated mRNA expression levels have been collected from embryos of trisomic and euploid mice and have been characterized by next-generation sequencing. We are identifying genomic locations with the most genetic dysregulation and comparing any variability within these sites based on the spatial as well as temporal differences in mRNA expression from tissues of trisomic and euploid samples. We hypothesize that genomic gene dysregulation sites will be tissue specific. Our study aims to explain how these perturbations in gene expression may affect certain DS phenotypes such as craniofacial abnormalities.