Browsing by Subject "phenotypes"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    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.
  • Thumbnail Image
    Item
    Evaluation of osteoclastogenesis in the Ts65Dn Down Syndrome Mouse Model
    (Office of the Vice Chancellor for Research, 2015-04-17) Abeysekera, Irushi S.; Raje, Kimaya; Roper, Randall J.
    Down Syndrome (DS) affects ~1 in 700 live births and is caused by trisomy of human chromosome 21 (Hsa21). DS is characterized by a wide spectrum of phenotypes including cognitive and skeletal abnormalities that affect all individuals with DS. To study these phenotypes, we utilize the Ts65Dn mouse model, which contains three copies of approximately half the gene orthologous found on Hsa21 and exhibits similar phenotypes as found in humans with DS. Individuals with DS and Ts65Dn mice have deficits in bone mineral density (BMD), bone architecture, and bone strength. Three copies of DYRK1A, a serine-threonine kinase encoded on Hsa21, has been linked to deficiencies in bone homeostasis in DS mouse models and individuals with DS. DYRK1A is thought to act via NFATc1, a master regulator of osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), a polyphenol found in high concentrations in green tea, is a known inhibitor of DYRK1A activity. We propose that the DS bone phenotype arises from an increase in osteoclastogenesis and/or maturation which results in increased bone resorption and disrupted bone homeostasis. We hypothesize that treatment of the mice during adolescence with 100 mg/kg/day EGCG would result in normalization of osteoclast numbers in trisomic mice to that of the controls. Osteoclast precursors from femur and spleen were isolated from 8-10 week old mice treated with 100 mg/kg/day EGCG or water from three weeks of age onwards. The cells were grown in the presence of M-CSF & RANK-L to promote osteoclast differentiation. Following 3 weeks in culture, the cells were fixed, TRAP stained, and multinucleated osteoclasts from control and Ts65Dn treated and untreated mice were counted. Mentor: Randall Roper, Department of Biology, IUPUI School of Science, Indianapolis, IN
  • Thumbnail Image
    Item
    Identification of associations between genotypes and longitudinal phenotypes via temporally-constrained group sparse canonical correlation analysis
    (Oxford, 2017-07) Hao, Xiaoke; Li, Chanxiu; Yan, Jingwen; Yao, Xiaohui; Risacher, Shannon L.; Saykin, Andrew J.; Shen, Li; Zhang, Daoqiang; Radiology and Imaging Sciences, School of Medicine
    Motivation: Neuroimaging genetics identifies the relationships between genetic variants (i.e., the single nucleotide polymorphisms) and brain imaging data to reveal the associations from genotypes to phenotypes. So far, most existing machine-learning approaches are widely used to detect the effective associations between genetic variants and brain imaging data at one time-point. However, those associations are based on static phenotypes and ignore the temporal dynamics of the phenotypical changes. The phenotypes across multiple time-points may exhibit temporal patterns that can be used to facilitate the understanding of the degenerative process. In this article, we propose a novel temporally constrained group sparse canonical correlation analysis (TGSCCA) framework to identify genetic associations with longitudinal phenotypic markers. Results: The proposed TGSCCA method is able to capture the temporal changes in brain from longitudinal phenotypes by incorporating the fused penalty, which requires that the differences between two consecutive canonical weight vectors from adjacent time-points should be small. A new efficient optimization algorithm is designed to solve the objective function. Furthermore, we demonstrate the effectiveness of our algorithm on both synthetic and real data (i.e., the Alzheimer’s Disease Neuroimaging Initiative cohort, including progressive mild cognitive impairment, stable MCI and Normal Control participants). In comparison with conventional SCCA, our proposed method can achieve strong associations and discover phenotypic biomarkers across multiple time-points to guide disease-progressive interpretation.
  • Thumbnail Image
    Item
    IDENTIFICATION OF TRANSCRIPTION FACTORS ASSOCIATED WITH DOWN SYNDROME SKELETAL ABNORMALITIES
    (Office of the Vice Chancellor for Research, 2012-04-13) Shepherd, Nicole; Deitz, Samantha; Roper, Randall J.
    Individuals with Down syndrome (DS) exhibit a variety of phenotypes, including craniofacial and skeletal dysmorphologies. It is believed that trisomic genes initiate phenotypes associated with Down syndrome, though specific gene-phenotype relationships for DS are largely unknown. We hypothesize that the altered expression of genes in three copies will also affect the expression of downstream genes, including non-trisomic genes and play an important role in DS phenotypes. Transcription factors, which encode proteins that bind to specific DNA sequences controlling the flow of transcription, are among the genes that may be affected by trisomy. We have identified genetic and phenotypic alterations in craniofacial precursors as early as embryonic dayE9.5of the Ts65Dn mouse model of human DS. This mouse model is trisomic for orthologs of approximately half of the genes on human chromosome 21. Previous microarray data from the developing mandible have shown dysregulation of multiple non-trisomic genes. We will test the expression of the Six2, Gata3, Gata6, Pth, Hoxb4, Runx2, Ets2, and Osterix transcription factors at two developmental time points, E9.5 and E13.5, to determine which are dysregulated in the Ts65Dn DS mouse model. Understanding the effect of trisomy on non-trisomic transcription factors will help identify links between trisomy and specific DS phenotypes.
  • Thumbnail Image
    Item
    MOLECULAR AND CELLULAR MECHANISMS LEADING TO SIMILAR PHENOTYPES IN DOWN AND FETAL ALCOHOL SYNDROMES
    (Office of the Vice Chancellor for Research, 2012-04-13) Solzak, Jeffrey P.; Zhou, Feng C.; Roper, Randall J.
    Down syndrome (DS) and Fetal Alcohol Syndrome (FAS) are two leading causes of birth defects with phenotypes ranging from cognitive impairment to craniofacial abnormalities. While DS originates from the trisomy of human chromosome 21 and FAS from prenatal alcohol consumption, many of the defining characteristics for these two disorders are stunningly similar. A sur-vey of the literature revealed over 20 similar craniofacial and structural defi-cits in both human and mouse models of DS and FAS. We hypothesized that the similar phenotypes observed are caused by disruptions in common mo-lecular or cellular pathways during development. To test our hypothesis, we examined morphometric, genetic, and cellular phenotypes during develop-ment of our DS and FAS mouse models at embryonic days 9.5-10.5. Our preliminary evidence indicates that during early development, dysregulation of Dyrk1a and Rcan1, cardinal genes affecting craniofacial and neurological precursors of DS, are also dysregulated in embryonic FAS models. Further-more, Caspase 3 was also found to have similar expression in DS and FAS craniofacial neural crest derived tissues such as the first branchial arch (BA1) and regions of the brain. This may explain a developmental deficit by means of increased apoptosis. We are currently investigating the expression of pAkt, a protein shown to be affected in FAS models, in cells located in these same craniofacial and neurological regions in DS models. Recent re-search shows that Ttc3, a gene that is triplicated and shown to be overex-pressed in our DS mouse model, targets pAkt in the nucleus affecting im-portant transcription factors regulating cell cycle and cell survival. While Akt has been shown to play a role in neuronal development, we hypothesize that it also affects similar cellular properties in craniofacial precursors during de-velopment. By comparing common genotypes and phenotypes of DS and FAS we may provide common mechanisms to target for potential treatments of both disorders.
  • Thumbnail Image
    Item
    MOLECULAR AND CELLULAR MECHANISMS LEADING TO SIMILAR PHENOTYPES IN DOWN AND FETAL ALCOHOL SYNDROMES
    (Office of the Vice Chancellor for Research, 2011-04-08) Solzak, Jeffrey P.; Zhou, Feng; Roper, Randall J.
    Down syndrome (DS) and Fetal Alcohol Syndrome (FAS) are two leading causes of birth defects with phenotypes ranging from cognitive impairment to craniofacial abnormalities. These syndromes have an estimated occurrence of 1/750 and 1/1000 live births, respectively. While DS originates from the trisomy of human chromosome 21 and FAS from excess alcohol consumption, many of the defining characteristics for these two disorders are stunningly similar. Our research of the published literature has identified more than 20 similarities in DS and FAS phenotypes including precise craniofacial and neurological abnormalities. We hypothesize that the similar phenotypes in these two syndromes are caused by disruptions in common molecular and cellular pathways. To test our hypothesis we are examining morphometric, genetic, and cellular phenotypes during development of DS and FAS mouse models. Our preliminary evidence indicates that during early development, expression of Dyrk1a and Rcan1 (two genes found in three copies in individuals with DS) is dysregulated in the craniofacial and neurological precursors of both DS and FAS as compared to normal control embryos. Using immuocytochemistry, we are analyzing cellular properties of neurological development in DS embryos and comparing deficiencies found between trisomic and normal mice to those found in FAS embryos at similar stages. These results will further define molecular and cellular alterations leading to DS and FAS phenotypes and provide mechanisms to target for potential pharmacotherapy.