Browsing by Subject "Gene dosage"

Now showing 1 - 5 of 5
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    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.
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    DEFA1A3 DNA gene-dosage regulates the kidney innate immune response during upper urinary tract infection
    (Cold Spring Harbor Laboratory, 2024-04-05) Canas, Jorge J.; Arregui, Samuel W.; Zhang, Shaobo; Knox, Taylor; Calvert, Christi; Saxena, Vijay; Schwaderer, Andrew L.; Hains, David S.; Pediatrics, School of Medicine
    Antimicrobial peptides (AMPs) are host defense effectors with potent neutralizing and immunomodulatory functions against invasive pathogens. The AMPs α-Defensin 1-3/DEFA1A3 participate in innate immune responses and influence patient outcomes in various diseases. DNA copy-number variations in DEFA1A3 have been associated with severity and outcomes in infectious diseases including urinary tract infections (UTIs). Specifically, children with lower DNA copy numbers were more susceptible to UTIs. The mechanism of action by which α-Defensin 1-3/DEFA1A3 copy-number variations lead to UTI susceptibility remains to be explored. In this study, we use a previously characterized transgenic knock-in of the human DEFA1A3 gene mouse to dissect α-Defensin 1-3 gene dose-dependent antimicrobial and immunomodulatory roles during uropathogenic Escherichia coli (UPEC) UTI. We elucidate the relationship between kidney neutrophil- and collecting duct intercalated cell-derived α-Defensin 1-3/DEFA1A3 expression and UTI. We further describe cooperative effects between α-Defensin 1-3 and other AMPs that potentiate the neutralizing activity against UPEC. Cumulatively, we demonstrate that DEFA1A3 directly protects against UPEC meanwhile impacting pro-inflammatory innate immune responses in a gene dosage-dependent manner.
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    Genetic and Developmental Basis of Cardiovascular Malformations
    (Elsevier, 2016-03) Azhar, Mohamad; Ware, Stephanie M.; Department of Pediatrics, IU School of Medicine
    Cardiovascular malformations (CVMs) are the most common birth defect, occurring in 1% to 5% of all live births. Genetic, epigenetic, and environmental factors all influence the development of CVMs, and an improved understanding of the causation of CVMs is a prerequisite for prevention. Cardiac development is a complex, multistep process of morphogenesis that is under genetic regulation. Although the genetic contribution to CVMs is well recognized, the genetic causes of human CVMs are still identified infrequently. This article discusses the key genetic concepts characterizing human CVMs, their developmental basis, and the critical developmental and genetic concepts underlying their pathogenesis.
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    Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts
    (MDPI, 2021-10-28) Thomas, Jared R.; Sloan, Kourtney; Cave, Kelsey; Wallace, Joseph M.; Roper, Randall J.; Biology, School of Science
    Trisomy 21 (Ts21) causes alterations in skeletal development resulting in decreased bone mass, shortened stature and weaker bones in individuals with Down syndrome (DS). There is a sexual dimorphism in bone mineral density (BMD) deficits associated with DS with males displaying earlier deficits than females. The relationships between causative trisomic genes, cellular mechanisms, and influence of sex in DS skeletal abnormalities remain unknown. One hypothesis is that the low bone turnover phenotype observed in DS results from attenuated osteoblast function, contributing to impaired trabecular architecture, altered cortical geometry, and decreased mineralization. DYRK1A, found in three copies in humans with DS, Ts65Dn, and Dp1Tyb DS model mice, has been implicated in the development of postnatal skeletal phenotypes associated with DS. Reduced copy number of Dyrk1a to euploid levels from conception in an otherwise trisomic Ts65Dn mice resulted in a rescue of appendicular bone deficits, suggesting DYRK1A contributes to skeletal development and homeostasis. We hypothesized that reduction of Dyrk1a copy number in trisomic osteoblasts would improve cellular function and resultant skeletal structural anomalies in trisomic mice. Female mice with a floxed Dyrk1a gene (Ts65Dn,Dyrk1afl/wt) were mated with male Osx-Cre+ (expressed in osteoblasts beginning around E13.5) mice, resulting in reduced Dyrk1a copy number in mature osteoblasts in Ts65Dn,Dyrk1a+/+/Osx-Cre P42 male and female trisomic and euploid mice, compared with littermate controls. Male and female Ts65Dn,Dyrk1a+/+/+ (3 copies of DYRK1A in osteoblasts) and Ts65Dn,Dyrk1a+/+/Osx-Cre (2 copies of Dyrk1a in osteoblasts) displayed similar defects in both trabecular architecture and cortical geometry, with no improvements with reduced Dyrk1a in osteoblasts. This suggests that trisomic DYRK1A does not affect osteoblast function in a cell-autonomous manner at or before P42. Although male Dp1Tyb and Ts65Dn mice exhibit similar skeletal deficits at P42 in both trabecular and cortical bone compartments between euploid and trisomic mice, female Ts65Dn mice exhibit significant cortical and trabecular deficits at P42, in contrast to an absence of genotype effect in female Dp1Tyb mice in trabecular bone. Taken together, these data suggest skeletal deficits in DS mouse models and are sex and age dependent, and influenced by strain effects, but are not solely caused by the overexpression of Dyrk1a in osteoblasts. Identifying molecular and cellular mechanisms, disrupted by gene dosage imbalance, that are involved in the development of skeletal phenotypes associated with DS could help to design therapies to rescue skeletal deficiencies seen in DS.
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    Skeletal health in DYRK1A syndrome
    (Frontiers Media, 2024-09-06) Otte, Elysabeth D.; Roper, Randall J.; Biology, School of Science
    DYRK1A syndrome results from a reduction in copy number of the DYRK1A gene, which resides on human chromosome 21 (Hsa21). DYRK1A has been implicated in the development of cognitive phenotypes associated with many genetic disorders, including Down syndrome (DS) and Alzheimer’s disease (AD). Additionally, overexpression of DYRK1A in DS has been implicated in the development of abnormal skeletal phenotypes in these individuals. Analyses of mouse models with Dyrk1a dosage imbalance (overexpression and underexpression) show skeletal deficits and abnormalities. Normalization of Dyrk1a copy number in an otherwise trisomic animal rescues some skeletal health parameters, and reduction of Dyrk1a copy number in an otherwise euploid (control) animal results in altered skeletal health measurements, including reduced bone mineral density (BMD) in the femur, mandible, and skull. However, little research has been conducted thus far on the implications of DYRK1A reduction on human skeletal health, specifically in individuals with DYRK1A syndrome. This review highlights the skeletal phenotypes of individuals with DYRK1A syndrome, as well as in murine models with reduced Dyrk1a copy number, and provides potential pathways altered by a reduction of DYRK1A copy number, which may impact skeletal health and phenotypes in these individuals. Understanding how decreased expression of DYRK1A in individuals with DYRK1A syndrome impacts bone health may increase awareness of skeletal traits and assist in the development of therapies to improve quality of life for these individuals.