Browsing by Author "Redmond, Rachael"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Assessment of Diabetes Clinical Trial Candidates Using Systems Pharmacology
    (Office of the Vice Chancellor for Research, 2016-04-08) Ali, Mohammed; Essex, Adam; Pham, Trang; Redmond, Rachael; Valdez, Sinai
    Curating molecular interactions is crucial to understanding how drugs work on molecular systems implicated in a disease and could provide future prospects for applications such as drug repositioning. For this project, we curated disease-specific drugs and protein interactions to help us understand Type II Diabetes in light of systems pharmacology. The pharmacological efficacy of drugs can be assessed based on their ability to regulate gene expressions in diabetic patients to resemble those of a healthy individual at a pathway level. Two drugs with a high level of similarity should share similar pharmacological effects, including drug target, side effects, mechanism of action, structure, and up or down-regulation of genes associated with diabetes. We focused on the relationships between drugs, proteins, and the disease, utilizing drug-drug similarity networks, a disease-specific protein-protein interaction network model, and the standardized curation of protein interactions by mining primary databases to visualize these relationships as they relate to Type II Diabetes. First, drugs were gathered from primary databases using proteins associated with the disease. From there, a drug-drug similarity network was constructed by examining similar targets, structures, side effects, and mechanism of action between drugs. To construct a disease-specific pathway model, proteins associated with Type II Diabetes were gathered from databases, PAG Electronic Repository and Connectivity-Maps, and analyzed from protein studies from the Diabetes Genome Anatomy Project and microarray datasets from Gene Expression Omnibus, generating a validated list of disease-specific proteins. Then, interactions and regulations within the proteins were determined to generate a diseasespecific protein-protein interaction model to provide insights to the disease itself and mechanisms of action of drugs related to Type II Diabetes. In the future, the drug-drug similarity network, the protein-protein interaction network model, and the protein and drug interactions could possibly aid in the repurposing of drugs for Type II Diabetes.
  • Thumbnail Image
    Item
    Pharmacological Dual Inhibition of Tumor and Tumor-Induced Functional Limitations in a Transgenic Model of Breast Cancer
    (American Association for Cancer Research, 2017-12) Wang, Ruizhong; Bhat-Nakshatri, Poornima; Padua, Maria B.; Prasad, Mayuri S.; Anjanappa, Manjushree; Jacobson, Max; Finnearty, Courtney; Sefcsik, Victoria; McElyea, Kyle; Redmond, Rachael; Sandusky, George; Penthala, Narsimha; Crooks, Peter A.; Liu, Jianguo; Zimmers, Teresa A.; Nakshatri, Harikrishna; Surgery, School of Medicine
    Breast cancer progression is associated with systemic effects, including functional limitations and sarcopenia without the appearance of overt cachexia. Autocrine/paracrine actions of cytokines/chemokines produced by cancer cells mediate cancer progression and functional limitations. The cytokine-inducible transcription factor NF-κB could be central to this process, as it displays oncogenic functions and is integral to the Pax7:MyoD:Pgc-1β:miR-486 myogenesis axis. We tested this possibility using the MMTV-PyMT transgenic mammary tumor model and the NF-κB inhibitor dimethylaminoparthenolide (DMAPT). We observed deteriorating physical and functional conditions in PyMT+ mice with disease progression. Compared with wild-type mice, tumor-bearing PyMT+ mice showed decreased fat mass, impaired rotarod performance, and reduced grip strength as well as increased extracellular matrix (ECM) deposition in muscle. Contrary to acute cachexia models described in the literature, mammary tumor progression was associated with reduction in skeletal muscle stem/satellite-specific transcription factor Pax7. Additionally, we observed tumor-induced reduction in Pgc-1β in muscle, which controls mitochondrial biogenesis. DMAPT treatment starting at 6 to 8 weeks age prior to mammary tumor occurrence delayed mammary tumor onset and tumor growth rates without affecting metastasis. DMAPT overcame cancer-induced functional limitations and improved survival, which was accompanied with restoration of Pax7, Pgc-1β, and mitochondria levels and reduced ECM levels in skeletal muscles. In addition, DMAPT restored circulating levels of 6 out of 13 cancer-associated cytokines/chemokines changes to levels seen in healthy animals. These results reveal a pharmacological approach for overcoming cancer-induced functional limitations, and the above-noted cancer/drug-induced changes in muscle gene expression could be utilized as biomarkers of functional limitations.