[CCoE Notice] PhD Defense: Pathological Crystallization from Mixed Aqueous - Organic Solvents

[Grayson, Audrey A]

PhD DEFENSE STUDENT: Megan Ketchum
DATE: Friday, December 2, 2016
TIME: 9:30 AM
PLACE:  Room N61, Engineering Building 1
DISSERTATION CHAIR: Dr. Jeffrey Rimer and Dr. Peter Vekilov
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TITLE:
Pathological Crystallization from Mixed Aqueous - Organic Solvents
Crystallization occurs under a variety of conditions including inside the human body. Many of these processes are undesirable diseases, which require pharmaceuticals or surgical procedures as treatment. Hematin, a toxic compound, crystallizes in malaria parasites to prevent eradication from the body while cholesterol crystallizes in the gallbladder and arteries creating blockages of vital fluids. In malaria, the parasite mutates to become resistant to current antimalarials while atherosclerosis exhibits no signs until heart attack, stroke or death. For these diseases, new pharmaceuticals are imperative as preventative medicine. However, knowledge of these phase changes is limited as no one has performed systematic studies to fundamentally understand crystallization or inhibition in physiologically relevant environments. With this knowledge, a platform for the design of potential drug compounds could be implemented.
For malaria, gallstones, and atherosclerosis, both lipid and aqueous media are present where crystallization transpires. For this study, the solution properties (solubilities in aqueous, organic and mixed aqueous-organic solvents) governing each pathological disease’s crystallization were scrutinized to elucidate the growth environment.

For malaria, current approaches to identify lead candidates rely on combinatorial methods employing parasite assays to screen compounds, which are incapable of elucidating the effect(s) of inhibitors on hematin crystallization. In this study, I use a physiologically-relevant growth medium (mixed aqueous-organic solution) to develop a facile, robust method of screening compounds that inhibit hematin crystal growth. As benchmarks, I selected antimalarials and antibiotics that are commonly used in combination therapies. I demonstrate that this assay can be used as a high-throughput platform to screen libraries of compounds as a more streamlined approach to identify inhibitors of pathological crystallization.
For atherosclerosis, I attempted to discern the crystal growth mechanism using in situ atomic force microscopy (AFM) in a mixed solvent. The surface features and polydispersity of cholesterol crystals are facilitated by the growth conditions (supersaturation, rate of cooling, etc.); therefore, bulk crystallization of cholesterol in the absence and presence of bile salts was performed to illustrate how natural compounds affect crystallization. While I was unable to reveal the crystal growth mechanisms and inhibiton, insight was gained for the future progression of this project.
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