- Browse by Subject
Browsing by Subject "genetic disorder"
Now showing 1 - 3 of 3
Results Per Page
Sort Options
Item Effect of EGCG on granule cell proliferation in the adult dentate gyrus of the Ts65Dn mouse(Office of the Vice Chancellor for Research, 2015-04-17) Sheikh, Zahir; Goodlett, Charles R.Down syndrome (DS) is the most common genetic disorder that results in cognitive abnormalities and occurs in approximately 1 in 700 live births. This disorder is caused by an extra copy of human chromosome 21 (Hsa21) which increases the dosage of the genes on that chromosome. Ts65Dn mice, which are the most studied mouse model for DS, are trisomic for segments of mouse chromosome 16 (Mmu16) which contain approximately half the genes found on Hsa21. These mice express some of the physical and behavioral abnormalities associated with DS. Previous research has shown impaired performance of Ts65Dn mice in hippocampaldependent tasks, such as in the radial arm maze task, compared to euploid control mice. Success in such tasks is thought to depend on the ability of the hippocampus to generate granule cells within the dentate gyrus. Young granule cells are highly active after integration and are required for memory formation. Previous research shows that Ts65Dn have a reduction in the formation of granule cells which leads us to hypothesize that Ts65Dn mice will perform worse in the radial arm maze compared to euploid controls. This leads us to conclude that Ts65Dn mice have reduced granule cell proliferation relative to controls. We are investigating the effects of EGCG, a polyphenolic component of green tea, on granule cell proliferation in adult mice. Different pathways are suggested to be effected by EGCG, such as by inhibiting Dyrk1a that is overproduced in DS mice or by up-regulation of the sonic hedgehog receptor Patched. Using BrdU peroxidase immunohistochemistry to label newly generated granule cells in the adult mouse dentate gyrus, we hypothesize that EGCG will increase cell proliferation in the granule cell layer of the dentate gyrus.Item Pioglitazone, an Insulin Sensitizing Drug, Attenuates the Development of Kidney and Liver Disease in the PCK Rodent Model of Polycystic Kidney Disease(Office of the Vice Chancellor for Research, 2010-04-09) Blazer-Yost, Bonnie L.; Haydon, Julie; Eggelston, Tracy; Chen, Jey-Hsin; Torres, Vicente E.; Gattone, VincentPolycystic kidney disease is a genetic disorder characterized by growth of fluid-filled cysts predominately in kidney and liver. The only treatment currently available is the removal/aspiration of the largest cysts or organ transplantation. Promising pharmaceutical agents in clinical trials interfere with the action of hormones that increase cAMP thereby inhibiting secretion of Cl-, and compensatory fluid flux, into the cysts. Other treatments proposed include chemotherapeutic and immunosuppressive drugs that interfere with cellular proliferation as well as with signaling pathways for Cl- secretion. Long-term use of these agents will have multiple side effects. Based on a recent observation that peroxisome proliferator activated receptor γ agonists such as Actos (pioglitazone) and Avandia (rosiglitazone) decrease mRNA levels of a Cl- transport protein and the Cl- secretory response to vasopressin stimulation in cultured renal cells, it is hypothesized that PPARγ agonists will inhibit cyst growth. The current studies show that a 7 or 14 week feeding regimen of 20 mg/Kg BW pioglitazone inhibits renal and hepatic bile duct cyst growth in a rodent model orthologous to human PKD. In addition, the degree of renal cortical fibrosis was diminished in the pioglitazone-treated animals after 14 weeks. These results suggest that PPARγ agonists may be effective in controlling both renal and hepatic cyst growth and renal fibrotic development in polycystic kidney disease.Item Testing Therapeutic Candidates in a Mouse Model of Polycystic Kidney Disease(Office of the Vice Chancellor for Research, 2016-04-08) McConkey, Shannon; Yang, Jenny; Bacallao, Robert; Berbari, Nicolas F.Approximately 1 in 500 middle aged people in the United States will be diagnosed with Polycystic Kidney Disease (PKD), an inherited genetic disorder that results in extreme cysts on the kidneys. PKD eventually leads to end-stage kidney failure and current treatments are limited to dialysis or transplantation. Thus, a pharmacological approach to prevent, delay, or slow the progression of PKD would revolutionize treatment and improve mortality. Interestingly, many proteins associated with PKD have been found in and around the primary cilia of renal epithelial cells. Cilia are small microtubule-based cellular appendages found on the surface of most cell types in the human body and are broadly classified as either “motile” or “primary” (immotile). Primary cilia are known to be mechano- and environmental sensors, and play a critical role in cell-to-cell communication. The aim of this proposed research is to use potential therapeutics identified in silico and in vitro in animal models of PKD to determine if the compound can delay or prevent cystogenesis. Here we test Sildenafil citrate (Viagra) in an animal model of rapidly progressing cyst formation for its ability to ameliorate the phenotype. Further research directed at understanding the cilia, cell-cycle, and cilia-mediated signalling activity will hopefully provide important insights into the mechanisms of renal cyst pathogenesis and lead to better approaches for therapeutic intervention for PKD.