The inaugural MIDD student symposium will take place on July 1st at 2:30 pm in CHEM110 (Chemistry Building). The event will give student affiliated with the MIDD the opportunity to present their work to other UWM students. We hold this event six times a year, bimonthly on the first Wednesday of the month at 2:30 pm. The presentation are 20 minutes long with 5 min Q&A. We have the following presentations:
Investigating the Impact of a Biofilm on the 3D Colony Formation of Breast Mammary Organoids
Fayzur Rhaman Khan from the Research Group of Prof. Qingsu Cheng, Department of Biomedical Engineering, College of Engineering and Applied Sciences, University of Wisconsin-Milwaukee
Biofilm is known for affecting human health. For example, colon cancer is largely associated with dysbiosis of gut microbiome and its association of biofilm formation. Likewise, biofilm formation could either increase or limit the therapeutic outcomes of treatment of breast diseases. However, the impact of biofilm on breast cancer initiation is neither well studied, nor a suitable coculture model exists. Therefore, we are inspired to engineer a 3D coculture model of biofilm and 3D mammary glands to bridge the gap.
We hypothesize that the in vivo impact of biofilm on the health of breast would be precisely recapitulated in a 3D in vitro coculture model. The objective of this study is to 1) engineer the model 2) examine the impact of a ProHealth and virulent biofilm on the growth and formation of 3D mammary epithelial cells.
To test this, we engineered a 3D biofilm–mammary organoid model by first establishing a bacterial biofilm on the surface of a 96-well plate, casing the biofilm with Matrigel, and then culturing MCF10A mammary epithelial cells on top using a 3D organoid-forming method. The coculture system was maintained for 7 days to evaluate epithelial colony growth and organization in the presence of a microbial-derived microenvironment.
Our results demonstrate 1) the success of engineering the coculture model and 2) virulent biofilm exacerbates organoids formation, and 3) ProHealth biofilm protects organoids formation form environmental stress. that the presence of a biofilm layer alters epithelial cell organization and growth patterns, suggesting that microbial-derived microenvironments may influence early cellular events associated with breast cancer progression.
Overall, this model provides a controlled platform to study biofilm– organoid interactions, to evaluate the modulatory role of probiotics in protecting mammary organoids from environmental stress, evaluate malignant potential of virulent biofilm.
Development of Novel Selective Serotonin Receptor 2B Antagonists
Maya Ruth Thom Fernando from the Research Group of Prof. Alexander (Leggy) Arnold, Department of Chemistry and Biochemisty, College of Letters and Science, University of Wisconsin-Milwaukee.
A palladium catalyzed Buchwald-Hartwig synthesis was used to generate new amine substituted benzodiazepines for the development of novel serotonin receptor antagonists. An optimized method has been developed using 5% Pd2(dba)3 in conjunction with 10% Xphos as the catalytic system. This method proves to be successful with substituted anilines, aliphatic amines and heterocyclic amines with yields ranging from 23% to 89%.
In collaboration with the Psychoactive Drug Screening Program, it was determined that some of these compounds are binding selectively the serotonin 2B receptor (5HT2B). The receptor is part of a larger serotonin receptor family containing multiple subtypes with almost identical structures, complicating the development of subtype selective ligands. Developing highly selective ligands is important because the serotonin receptor subtypes are expressed tissue specifically, mediating specific physiological processes. Our most promising compound has a Ki of 62 nM for 5HT2B with 15-fold selectivity over 5HT2C and does not bind 5HT2A.
Functional cell-based assays identified this compound as antagonist enabling the development of new treatments for cardiopulmonary diseases, including pulmonary arterial hypertension (PAH) and valvular heart disease (VAD). We present the synthesis and preclinical characterization of a large number of related compounds with a clear structure-activity relationship. In addition, computational approaches aid our understanding of subtype selectivity. Overall, our findings confirm the adaptability of the benzodiazepine scaffold for developing new GPCR ligands without any affinity to the GABA(A) receptors.