IU Indianapolis ScholarWorks :: Browsing by Author "Roper, Randall J."

Browsing by Author "Roper, Randall J."

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3D Assessment of Nasopharyngeal and Craniofacial Phenotypes in Ts65Dn Down Syndrome Mice Treated with a Dyrk1a Inhibitor
(2014-04-11) Starbuck, John M.; Harrington, Emily; Kula, Katherine S.; Ghoneima, Ahmed A.; Roper, Randall J.
Background: Down syndrome (DS) originates from having three copies of chromosome 21 (i.e. Trisomy 21). DS is associated with many detrimental phenotypes including intellectual disabilities, heart defects, abnormal craniofacial development, and obstructive sleep apnea, which develops from restricted nasopharyngeal airways and an underdeveloped mandible. Ts65Dn mice are trisomic for about half of the orthologs on human chromosome 21 and display many phenotypes associated with DS including craniofacial abnormalities. Dyrk1a is found in three copies in Ts65Dn mice and individuals with DS, and thought to be a root cause of the craniofacial phenotypes. Epigallocatechin 3-gallate (EGCG) is a green tea polyphenol and inhibitor of Dyrk1a activity. Purpose: We hypothesize that decreased Dyrk1a activity in Ts65Dn mice will ameliorate craniofacial dysmorphology. Methods: To test our hypothesis we compared Ts65Dn mice with two or three copies of Dyrk1a and compared Ts65Dn mice with and without prenatal EGCG treatment. EGCG treated mothers were fed 200mg/kg EGCG on gestational day 7. Six week old mice were sacrificed and their heads imaged using micro-computed tomography (μCT). From μCT images, we measured nasopharyngeal airway volume and anatomical landmarks (n = 54) from the facial skeleton, cranial vault, cranial base, and mandible. Mean nasopharyngeal airway volumes were graphically compared, and a landmark-based multivariate geometric morphometric approach known as Euclidean Distance Matrix Analysis (EDMA) was carried out to assess local differences in craniofacial morphology between trisomic mouse samples. Results: Our preliminary results indicate that EGCG treatment and reduced Dyrk1a copy number increases mean nasopharyngeal airway volume in Ts65Dn mice. Craniofacial morphometric differences were found among all samples. EGCG treatment increased portions of the mandible and decreased portions of the cranial vault and cranial base. Conclusion: Preliminary analyses suggest that both EGCG treatment and reduced Dyrk1a copy number affect craniofacial morphology.
A new Down syndrome rat model races forward
(Elsevier, 2022) Roper, Randall J.; Goodlett, Charles R.; Biology, School of Science
Animal models of Down syndrome (DS) provide an essential resource for understanding genetic, cellular, and molecular contributions to traits associated with trisomy 21 (Ts21). Recent genetic enhancements in the development of DS models, including the new TcHSA21rat model (Kazuki et al.), have potential to transform our understanding of and potential therapies for Ts21.
Abnormal mineralization of the Ts65Dn Down syndrome mouse appendicular skeleton begins during embryonic development in a Dyrk1a-independent manner
(Elsevier, 2015-05) Blazek, Joshua D.; Malik, Ahmed M.; Tischbein, Maeve; Arbones, Maria L.; Moore, Clara S.; Roper, Randall J.; Biology, School of Science
The relationship between gene dosage imbalance and phenotypes associated with Trisomy 21, including the etiology of abnormal bone phenotypes linked to Down syndrome (DS), is not well understood. The Ts65Dn mouse model for DS exhibits appendicular skeletal defects during adolescence and adulthood but the developmental and genetic origin of these phenotypes remains unclear. It is hypothesized that the postnatal Ts65Dn skeletal phenotype originates during embryonic development and results from an increased Dyrk1a gene copy number, a gene hypothesized to play a critical role in many DS phenotypes. Ts65Dn embryos exhibit a lower percent bone volume in the E17.5 femur when compared to euploid embryos. Concomitant with gene copy number, qPCR analysis revealed a ~1.5 fold increase in Dyrk1a transcript levels in the Ts65Dn E17.5 embryonic femur as compared to euploid. Returning Dyrk1a copy number to euploid levels in Ts65Dn, Dyrk1a+/− embryos did not correct the trisomic skeletal phenotype but did return Dyrk1a gene transcript levels to normal. The size and protein expression patterns of the cartilage template during embryonic bone development appear to be unaffected at E14.5 and E17.5 in trisomic embryos. Taken together, these data suggest that the dosage imbalance of genes other than Dyrk1a is involved in the development of the prenatal bone phenotype in Ts65Dn embryos.
ANALYSIS OF CO-OCCURRING PHENOTYPES IN INFANTS WITH DOWN SYNDROME WITH CARDIAC DEFECTS
(Office of the Vice Chancellor for Research, 2011-04-08) Shepherd, Nicole; Duvall, Nichole; Stone, Sandra B.; Davis, Charlene; Stanley, Maria; Roper, Randall J.
Down syndrome (DS), caused by a trisomy 21, is the most common chromosomal aneuploidy occurring in approximately 1 of 750 live births. Individuals with DS exhibit craniofacial dysmorphology, cardiac defects, gastrointestinal problems, and cognitive impairment, although these phenotypes vary in incidence and severity. Common cardiac defects are usually recognized in young infants with DS and include atrial septal anomalies, ventricular septal abnormalities, atrioventricular canal defects, and patent ductus arteriosus. Additional abnormalities may also affect infants with DS, but not be identified until later in life. Since multiple phenotypes are found in these individuals, we hypothesize that children with a severe congenital heart defect may be at increased risk for additional medical issues. To investigate this hypothesis, we performed a retrospective chart review of 170 infants with DS between birth and 6 months of age who were referred to the Down Syndrome Program at Riley Hospital for Children from August 2005 to July 2010. We analyzed comorbidity in infants with upper airway obstruction (UAO) or a feeding problem with and without a severe congenital heart defect. Our data show that 33% of infants without a cardiac defect have identified UAO while 44% with a severe cardiac defect have identified UAO. Additionally, 59% of infants without a cardiac defect compared to 49% with a severe cardiac defect have a feeding problem. With the knowledge of these comorbid clinical features in DS, healthcare providers may be able to identify potential complications affecting infants with DS earlier in life.
Behavioral Phenotyping for Down Syndrome in Mice
(Wiley, 2020-09) Roper, Randall J.; Goodlett, Charles R.; Martínez de Lagrán, María; Dierssen, Mara; Biology, School of Science
Down syndrome (DS) is the most frequent genetic cause of intellectual disability, characterized by alterations in different behavioral symptom domains: neurodevelopment, motor behavior, and cognition. As mouse models have the potential to generate data regarding the neurological basis for the specific behavioral profile of DS, and may indicate pharmacological treatments with the potential to affect their behavioral phenotype, it is important to be able to assess disease-relevant behavioral traits in animal models in order to provide biological plausibility to the potential findings. The field is at a juncture that requires assessments that may effectively translate the findings acquired in mouse models to humans with DS. In this article, behavioral tests are described that are relevant to the domains affected in DS. A neurodevelopmental behavioral screen, the balance beam test, and the Multivariate Concentric Square Field test to assess multiple behavioral phenotypes and locomotion are described, discussing the ways to merge these findings to more fully understand cognitive strengths and weaknesses in this population. New directions for approaches to cognitive assessment in mice and humans are discussed.
Can Epigallocatechin gallate (EGCG) Treatment Rescue Hippocampal-Dependent Cognitive Function in a Down Syndrome Mouse Model?
(Office of the Vice Chancellor for Research, 2016-04-08) East, Audrey; Stringer, Megan; Abeysekera, Irushi; Goodlett, Charles R.; Roper, Randall J.
Down Syndrome (DS) is caused by the trisomy of human chromosome 21 (Hsa21). Trisomy 21 can cause various behavioral, cognitive, learning and memory deficits. Deficits in hippocampal structure and function have been identified in mouse models of DS and are implicated in cognitive and learning impairments. Mouse models have suggested that deficits in cognitive function are associated with overexpression of Dyrk1a, a gene on Hsa21 found in three copies of individuals with DS. Dyrk1a is a gene that is involved in brain development and function. Ts65Dn DS model mice exhibit trisomy for approximately half of the genes on Hsa21 including Dyrk1a and exhibit cognitive and learning impairments. We are using Ts65Dn mice to test the effects of Epigallocatechin gallate (EGCG), a Dyrk1a inhibitor, on Dyrk1a activity and cognitive function. We hypothesize that EGCG will reduce Dyrk1a activity in the hippocampus and improve hippocampal-dependent spatial learning and memory in the Morris water maze place learning task in Ts65Dn mice. The mice were given daily EGCG treatment (200 mg/kg per day) by means of oral gavage beginning on postnatal day 54 and continuing throughout water maze testing (postnatal days 67-74). Measures of spatial learning included latency and path length to find a submerged platform during acquisition trials (postnatal days 67-73). Memory for the previously learned location of the platform was assessed on a probe trial (postnatal day 74) in which the platform was removed and the amount of time spent swimming in the area of the tank previously containing the platform was measured. These measures allowed us to analyze the mice’s ability to learn and remember the position of the platform and to spatially orient themselves. Preliminary data indicates that EGCG treatment may not be an effective treatment for the spatial learning and memory deficits evident in this mouse model of DS.
Characterizing Femoral Structure of the Ts66Yah Mouse Model of Down Syndrome
(2023-08) Sloan, Kourtney; Roper, Randall J.; Li, Jiliang; McNulty, Margaret A.; Picard, Christine J.
Down syndrome (DS) is caused by the partial or complete trisomy of human chromosome 21 (Hsa21) and can result in skeletal deficits, including lower bone mineral density (BMD) and increased risk of fracture and osteoporosis or osteopenia earlier than the general population. Mouse models of DS have been developed to understand the genetic mechanisms resulting in these phenotypes, but models differ due to the complex genetic nature of DS and differing genome structures between humans and mice. Ts65Dn mice have been a popular model of DS as they contain ~50% of Hsa21 orthologous genes on a freely segregating minichromosome, but there is speculation that the phenotypes are exaggerated by non-Hsa21 orthologous trisomic genes also present. To address this issue, the Ts66Yah mouse model was developed to remove the non-Hsa21 orthologous trisomic genes. In this study, male and female Ts66Yah mouse femurs were evaluated during bone accrual and peak bone mass to investigate structural differences using micro-computed tomography. Additionally, the role of trisomic Dyrk1a, a Hsa21 gene previously linked to bone deficits in Ts65Dn mice, was evaluated through genetic and pharmacological means in Ts66Yah femurs at postnatal day 36. Ts66Yah mice were found to have little or no trabecular deficits at any age evaluated, but sex-dependent cortical deficits were present at all ages investigated. Reducing Dyrk1a copy number in Ts66Yah mice significantly improved cortical deficits but did not return cortical bone to euploid levels. Pharmacological treatment with DYRK1A inhibitor L21 was confounded by multiple variables, making it difficult to draw conclusions about DYRK1A inhibition in this manner. Overall, these results indicate trabecular deficits associated with Ts65Dn mice may be due to the non-Hsa21 orthologous trisomic genes, and more Hsa21 orthologous trisomic genes are necessary to produce trabecular deficits in DS model mice. As more mouse models of DS are developed, multiple models need to be assessed to accurately define DS-associated phenotypes and test potential treatments.
Clinical identification of feeding and swallowing disorders in 0-6 month old infants with Down syndrome
(Wiley, 2019-02) Stanley, Maria A.; Shepherd, Nicole; Duvall, Nichole; Jenkinson, Sandra B.; Jalou, Hasnaa E.; Givan, Deborah C.; Steele, Gregory H.; Davis, Charlene; Bull, Marilyn J.; Watkins, Donna U.; Roper, Randall J.; Pediatrics, School of Medicine
Feeding and swallowing disorders have been described in children with a variety of neurodevelopmental disabilities, including Down syndrome (DS). Abnormal feeding and swallowing can be associated with serious sequelae such as failure to thrive and respiratory complications, including aspiration pneumonia. Incidence of dysphagia in young infants with DS has not previously been reported. To assess the identification and incidence of feeding and swallowing problems in young infants with DS, a retrospective chart review of 174 infants, ages 0-6 months was conducted at a single specialty clinic. Fifty-seven percent (100/174) of infants had clinical concerns for feeding and swallowing disorders that warranted referral for Videofluroscopic Swallow Study (VFSS); 96/174 (55%) had some degree of oral and/or pharyngeal phase dysphagia and 69/174 (39%) had dysphagia severe enough to warrant recommendation for alteration of breast milk/formula consistency or nonoral feeds. Infants with certain comorbidities had significant risk for significant dysphagia, including those with functional airway/respiratory abnormalities (OR = 7.2). Infants with desaturation with feeds were at dramatically increased risk (OR = 15.8). All young infants with DS should be screened clinically for feeding and swallowing concerns. If concerns are identified, consideration should be given to further evaluation with VFSS for identification of dysphagia and additional feeding modifications.
Correction of cerebellar movement related deficits by normalizing Dyrk1a copy number in the Ts65Dn mouse model for Down syndrome
(Office of the Vice Chancellor for Research, 2016-04-08) Patel, Roshni; Stringer, Megan; Abeysekera, Irushi; Roper, Randall J.; Goodlett, Charles R.
Elucidation of the underlying mechanisms involved in brain related deficits of Down syndrome (DS) would be useful for consideration of therapeutic interventions. Several DSspecific phenotypes have been hypothesized to be linked to altered expression or function of specific trisomic genes. One such gene of interest is D YRK1A , which has been implicated in behavioral functions of the hippocampus and cerebellum. The Ts65Dn mouse model for DS includes a triplication of D yrk1a in addition to a triplication of >100 other human chromosome 21 mouse orthologs. To evaluate the role of D yrk1a in cerebellar function, we have genetically normalized the D yrk1a copy number in otherwise trisomicTs65Dn mice and reduced D yrk1a copy number in otherwise euploid mice (2N) for a total of 3 alternative genetic doses of D yrk1a: EuploidDyrk1a +/+ , EuploidDyrk1a +/, Ts65DnDyrk1a +/+/+ , and Ts65DnDyrk1a +/+/. Cerebellar movementrelated function in these knockdown models is being assessed through a novel behavioral balance beam task. Additionally, levels of D yrk1a activity in the cerebellum for all genotypes were analyzed by HPLC. We have previously demonstrated that Ts65DnDyrk1a +/+/+ mice perform worse in the balance beam task in comparison to EuploidDyrk1a +/+ mice. Preliminary results of the current study do not indicate such a difference among Ts65DnDyrk1a +/+/+ mice in comparison to EuploidDyrk1a +/+ mice. We hypothesize that the lack of replication of the previous findings may be due to differences in postweaning housing environments. Mice in the previous study were singlehoused, whereas mice in the present study were grouphoused, which may help mitigate motor deficits in the trisomic mice. Additionally, current trends display a deficit in balance beam performance of both the EuploidDyrk1a +/and the Ts65DnDyrk1a +/+/groups, which suggests that reducing the copy number of D yrk1a by one may have detrimental effects on motor coordination. Concomitant analysis of the balance beam performances and Dyrk1a activity levels may indicate the sensitivity of the balance beam task to assess the role Dyrk1a activity in cerebellar function.
Correction of Craniofacial Deficits using Epigallocatechin-3’-gallate Treatment in a Down Syndrome Mouse Model
(Office of the Vice Chancellor for Research, 2014-04-11) Tumbleson, Danika M.; Haley, Emily M.; Diallo, Mariyamou; Deitz, Samantha L.; Roper, Randall J.
Down syndrome (DS) is caused by trisomy of human chromosome (HSA21). Individuals with DS display distinct craniofacial abnormalities including an undersized, dismorphic mandible which leads to difficulty with eating, breathing, and swallowing. Using the Ts65Dn DS mouse model (three copies of ~50% HSA21 homologs), we have traced the mandibular deficit to a neural crest cell (NCC) deficiency and reduction in first pharyngeal arch (PA1 or mandibular precursor) at embryonic day 9.5. Previous studies have shown that this deficit is caused when NCC fail to migrate from the neural tube to populate the PA1 and fail to proliferate in the PA1. At E9.5, Dyrk1A, a triplicated DS candidate gene, is overexpressed in the PA1 and may cause the NCC and PA1 deficits. We hypothesize that treatment of pregnant Ts65Dn mothers with Epigallocatechin-3’-gallate (EGCG), a known Dyrk1A inhibitor, will correct NCC deficits and rescue the undersized PA1 in trisomic E9.5 embryos. To test our hypothesis, we treated pregnant Ts65Dn mothers with EGCG, where embryos received treatment from either E7-E8 or E0-E9.5. Our preliminary study found variable increases in PA1 volume and NCC number between treatment regimens, with several treatment groups indicating EGCG treatment has the potential to rescue the NCC deficit in the mandibular precursor. We found an increase in NCC number and PA1 volume with E7-E8 EGCG treatment in 21-24 somite embryos from trisomic mothers and in euploid embryos from euploid mothers treated from E0-E9.5. With EGCG treatment, we also observed a decrease in the average somite number of embryos from trisomic mothers, but an increase in those mothers’ average litter size. This study is important because it helps define the specific dosage and timing of ECGC and how it may affect specific DS phenotypes. These findings provide preclinical testing for a potential therapy for craniofacial disorders linked to DS.

Browsing by Author "Roper, Randall J."

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