Browsing by Author "Shadmand, Mehdi"
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Item Drug Discovery Through Drug Perturbation Pathway Modeling and Network Analysis(Office of the Vice Chancellor for Research, 2014-04-11) Ho, Tung; Hakola, Krista; Wagle, Pragat; Rouse, Evan; Shadmand, Mehdi; Han, Juyeon; Ibrahim, SaraDue to intrinsic complex molecular interactions, the “one disease – one target – one drug” strategy for disease treatment is no longer the best option to treat cancers. To assess drug pharmacological effects, we assume that “ideal” drugs for a patient can treat or prevent the disease by modulating gene expression profiles of this patient to the similar level with those in healthy people. A new approach for drug-protein interactions curation, drug-drug similarity network comparison, and integrative pathway model construction and evaluation was introduced to determine optimal drugs for various cancers. Drug-protein interaction curation is conducted to discover novel drug-protein relationships and is categorized as: up regulated, down regulated, indirect up or down, ambiguous and unknown. The manual curation can be utilized for drug repurposing and examining drug mechanism on a pathway level. A drug-drug similarity network model is built by examining similar targets, therapeutic mechanisms, side effects, and chemical structures. Drug similarity analysis is useful for drug repositioning because similar drugs may have compatible therapeutic or toxic effects for a disease. Drug similarity networks are constructed and examined through a molecular network visualization platform. An integrative disease-specific pathway model is also built to gain a more holistic view of disease mechanisms by including every significant disease-specific protein. Including drugs on the pathway through target information can also offer a clear mechanism for the drug’s action. We also transform integrated pathways into network models and ranked drugs based on the network topological features of drug targets, drug-affecting genes/proteins, and curated disease-specific proteins. Combining our three approaches could potentially lead to advances in drug repurposing and repositioning.Item Ferrochelatase is a therapeutic target for ocular neovascularization(Wiley, 2017) Basavarajappa, Halesha D.; Sulaiman, Rania S.; Qi, Xiaoping; Shetty, Trupti; Babu, Sardar Sheik Pran; Sishtla, Kamakshi L.; Lee, Bit; Quigley, Judith; Alkhairy, Sameerah; Briggs, Christian M.; Gupta, Kamna; Tang, Buyun; Shadmand, Mehdi; Grant, Maria B.; Boulton, Michael E.; Seo, Seung-Yong; Corson, Timothy W.; Department of Ophthalmology, IU School of MedicineOcular neovascularization underlies major blinding eye diseases such as “wet” age-related macular degeneration (AMD). Despite the successes of treatments targeting the vascular endothelial growth factor (VEGF) pathway, resistant and refractory patient populations necessitate discovery of new therapeutic targets. Using a forward chemical genetic approach, we identified the heme synthesis enzyme ferrochelatase (FECH) as necessary for angiogenesis in vitro and in vivo. FECH is overexpressed in wet AMD eyes and murine choroidal neovascularization; siRNA knockdown of Fech or partial loss of enzymatic function in the Fechm1Pas mouse model reduces choroidal neovascularization. FECH depletion modulates endothelial nitric oxide synthase function and VEGF receptor 2 levels. FECH is inhibited by the oral antifungal drug griseofulvin, and this compound ameliorates choroidal neovascularization in mice when delivered intravitreally or orally. Thus, FECH inhibition could be used therapeutically to block ocular neovascularization.Item Kif14 overexpression accelerates murine retinoblastoma development(Wiley, 2016-10) O'Hare, Michael; Shadmand, Mehdi; Sulaiman, Rania S.; Sishtla, Kamakshi; Sakisaka, Toshiaki; Corson, Timothy W.; Department of Ophthalmology, IU School of MedicineThe mitotic kinesin KIF14 has an essential role in the recruitment of proteins required for the final stages of cytokinesis. Genomic gain and/or overexpression of KIF14 has been documented in retinoblastoma and a number of other cancers, such as breast, lung and ovarian carcinomas, strongly suggesting its role as an oncogene. Despite evidence of oncogenic properties in vitro and in xenografts, Kif14's role in tumor progression has not previously been studied in a transgenic cancer model. Using a novel Kif14 overexpressing, simian virus 40 large T-antigen retinoblastoma (TAg-RB) double transgenic mouse model, we aimed to determine Kif14's role in promoting retinal tumor formation. Tumor initiation and development in double transgenics and control TAg-RB littermates were documented in vivo over a time course by optical coherence tomography, with subsequent ex vivo quantification of tumor burden. Kif14 overexpression led to an accelerated initiation of tumor formation in the TAg-RB model and a significantly decreased tumor doubling time (1.8 vs. 2.9 weeks). Moreover, overall percentage tumor burden was also increased by Kif14 overexpression. These data provide the first evidence that Kif14 can promote tumor formation in susceptible cells in vivo.Item Observations on spontaneous tumor formation in mice overexpressing mitotic kinesin Kif14(Nature, 2018) Sishtla, Kamakshi; Pitt, Natalie; Shadmand, Mehdi; O'Hare, Michael N.; Sulaiman, Rania S.; Sinn, Anthony L.; Condon, Keith; Pollok, Karen E.; Sandusky, George E.; Corson, Timothy W.; Ophthalmology, School of MedicineThe KIF14 locus is gained and overexpressed in various malignancies, with prognostic relevance. Its protein product, a mitotic kinesin, accelerates growth of normal mammary epithelial cells in vitro and retinoblastoma tumours in a mouse model, while KIF14 knockdown blocks growth of brain, liver, ovarian, breast, prostate, and other tumour cells and xenografts. However, the tumour-initiating effects of Kif14 overexpression have not been studied. We aged a cohort of Kif14-overexpressing transgenic mice and wild-type littermates and documented survival, cause of death, and tumour burden. The Kif14 transgene was expressed in all tissues examined, and was associated with increased proliferation marker expression. Neither mouse weights nor overall survival differed between genotypes. However, Kif14 transgenic mice showed a higher incidence of fatal lymphomas (73 vs. 50%, p = 0.03, Fisher’s exact test), primarily follicular and diffuse B-cell lymphomas. Non-tumour findings included a bilateral ballooning degeneration of lens in 12% of Kif14 transgenic mice but no wild-type mice (p = 0.02). Overall, this work reveals a novel association of Kif14 overexpression with lymphoma but suggests that Kif14 does not have as prominent a role in initiating cancer in other cell types as it does in accelerating tumour development in response to other oncogenic insults.Item Optical coherence tomography enables imaging of tumor initiation in the TAg-RB mouse model of retinoblastoma(Molecular Vision, 2015) Wenzel, Andrea A.; O'Hare, Michael N.; Shadmand, Mehdi; Corson, Timothy W.; Department of Ophthalmology, IU School of MedicinePURPOSE: Retinoblastoma is the most common primary intraocular malignancy in children. Although significant advances in treatment have decreased mortality in recent years, morbidity continues to be associated with these therapies, and therefore, there is a pressing need for new therapeutic options. Transgenic mouse models are popular for testing new therapeutics as well as studying the pathophysiology of retinoblastoma. The T-antigen retinoblastoma (TAg-RB) model has close molecular and histological resemblance to human retinoblastoma tumors; these mice inactivate pRB by retinal-specific expression of the Simian Virus 40 T-antigens. Here, we evaluated whether optical coherence tomography (OCT) imaging could be used to document tumor growth in the TAg-RB model from the earliest stages of tumor development. METHODS: The Micron III rodent imaging system was used to obtain fundus photographs and OCT images of both eyes of TAg-RB mice weekly from 2 to 12 weeks of age and at 16 and 20 weeks of age to document tumor development. Tumor morphology was confirmed with histological analysis. RESULTS: Before being visible on funduscopy, hyperreflective masses arising in the inner nuclear layer were evident at 2 weeks of age with OCT imaging. After most of these hyperreflective cell clusters disappeared around 4 weeks of age, the first tumors became visible on OCT and funduscopy by 6 weeks. The masses grew into discrete, discoid tumors, preferentially in the periphery, that developed more irregular morphology over time, eventually merging and displacing the inner retinal layers into the vitreous. CONCLUSIONS: OCT is a non-invasive imaging modality for tracking early TAg-RB tumor growth in vivo. Using OCT, we characterized TAg-positive cells as early as 2 weeks, corresponding to the earliest stages at which tumors are histologically evident, and well before they are evident with funduscopy. Tracking tumor growth from its earliest stages will allow better analysis of the efficacy of novel therapeutics and genetic factors tested in this powerful mouse model.Item Pseudomonas Aeruginosa Biofilm Formation in Different Environments(Office of the Vice Chancellor for Research, 2013-04-05) Shadmand, Mehdi; Anderson, Gregory G.Various bacteria, such as the soil microbe Pseudomonas aeruginosa, form into strong structures to defend themselves from antibiotics and other harmful materials. These structures are called biofilms. The goal of this research is to isolate P. aeruginosa from several soil samples and determine whether they are able to form biofilms in those environments. Another goal of this research is to find out how different environmental factors affect the formation of Pseudomonas biofilms. We isolated P. aeruginosa from soil samples using Pseudomonas Isolation Agar plates. The colonies most similar to P. aeruginosa were picked, cultured, and tested by PCR in order to confirm that the strains were actually P. aeruginosa. Using these methods, so far we have collected 12 P. aeruginosa strains and we are collecting more strains from different soil samples. In future studies, we will determine whether these strains form biofilms in soil. We will also demonstrate the effect of magnesium on P. aeruginosa on biofilm formation. These studies will begin to investigate how altering environmental conditions can influence persistence of this bacterial pathogen in the soil. These studies can have broad implications for transmission of the bacterium from the environment to humans during disease.Item Synthesis and Biological Evaluation of Novel Homoisoflavonoids for Retinal Neovascularization(ACS, 2015-06) Basavarajappa, Halesha D.; Lee, Bit; Lee, Hyungjun; Sulaiman, Rania S.; An, Hongchan; Magaña, Carlos; Shadmand, Mehdi; Vayl, Alexandra; Rajashekhar, Gangaraju; Kim, Eun-Yeong; Suh, Young-Ger; Lee, Kiho; Seo, Seung-Yong; Corson, Timothy W.; Department of Ophthalmology, IU School of MedicineEye diseases characterized by excessive angiogenesis such as wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity are major causes of blindness. Cremastranone is an antiangiogenic, naturally occurring homoisoflavanone with efficacy in retinal and choroidal neovascularization models and antiproliferative selectivity for endothelial cells over other cell types. We undertook a cell-based structure–activity relationship study to develop more potent cremastranone analogues, with improved antiproliferative selectivity for retinal endothelial cells. Phenylalanyl-incorporated homoisoflavonoids showed improved activity and remarkable selectivity for retinal microvascular endothelial cells. A lead compound inhibited angiogenesis in vitro without inducing apoptosis and had efficacy in the oxygen-induced retinopathy model in vivo.Item Utilizing the C2Maps Platform for Characterizing Drug-Protein Relations, Generating Mobile Games, and Constructing Integrated Pathway Models(Office of the Vice Chancellor for Research, 2013-04-05) Shadmand, Mehdi; Wen, Dian; Wagle, Pragat; Stark, Ryan; Smith, Ashley; Ibrahim, SaraThe C2Maps platform is a collection of genome-wide data that display the connections between drugs, diseases and genes. The C2Maps is used as a tool to compare and extrapolate known map data into unknown areas. By using C2Maps, researchers can compare genetic, sequential and physical information about disease specific proteins. Manual curation is important for the C2Maps platform in order to validate the literature mining approach and to overcome high levels of data noise generated from molecular networks. Currently we are examining specific drug-protein relationships in several diseases. In this research, the C-Maps website is being used to manually curate abstracts about disease specific drugprotein relations and then it is determined whether a drug “Up Regulates”, “Down Regulates”, or “Indirectly” affects a specific protein. Presently, more than 2000 specific protein-drug relations have been examined through the platform. We theorize that new drug-protein relations will be discovered through curation efforts. To broaden the scope of curation data generated, a C2Maps mobile game is in the process of being developed. This game takes advantage of novel technology in mobile development to create a game that will allow several researchers to contribute to the curation process. The data generated from the manual curation approach can be used to validate various protein-drug relationships in pharmacology and can determine the best possible drugs targeting specific proteins in cancer. Optimal drugs and their respective targets for a specific disease can then be incorporated into an integrative pathway model to analyze the mechanism of the drug. Specific properties of the drug, including chemical structure, can then be examined to determine how a specific drug acts on particular target proteins.