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Understanding cellular behavior at the molecular level is often the key to understanding human disease. Our researchers who are investigating at the cellular and molecular level further the understanding of the molecular mechanisms of cells to guide the development of the next generation of diagnostics and therapeutics for such diseases as diabetes and cancer.
Autoimmune disease occurs when one's own body mounts an immune-inflammatory response against its own tissues. This set of diseases includes Graves' disease and Hashimoto's disease, both pathologies of the thyroid; colitis, which is a pathological inflammation of the intestine; and diabetes. A highly collaborative group involving Kelly McCall, assistant professor of endocrinology, Ramiro Malgor, associate professor of pathology, Fabian Benencia, associate professor of immunology, Frank Schwartz, J.O. Watson Endowed Chair for Diabetes Research and professor of endocrinology, and Douglas Goetz, professor of chemical and biomolecular engineering, seeks to identify the molecular mechanisms that underlie autoimmune-inflammatory disease, then exploit the understanding to develop novel diagnostics and therapeutics.
The current focus is on the role of Toll-Like Receptors (TLRs) in pathogenesis and progression. Recently, this group has found evidence that TLRs may be operative in certain cancers, suggesting a link between autoimmunity and cancer. TLRs have also been implicated in atherosclerosis (hardening of the arteries), and the group is actively exploring the molecular alterations that occur in the vasculature as an atherosclerotic plaque develops. This latter effort involves Mitch Silver, DO, of MidOhio Cardiology and Vascular Consultants.
The tumor microenvironment subverts the function of immune cells, thus using the same cells in charge of rejecting the tumor to promote its growth. A central issue in tumor immunology is to identify the decisive factors that determine the immunosuppressive status of tumor-associated antigen-presenting cells. Novel mechanistic insights into the processes of antigen-presenting cell differentiation and activation are likely to have potential impact also in the field of tumor immunology and immunotherapy. Fabian Benencia, associate professor of immunology, and Kelly McCall, assistant professor of endocrinology, investigate the effect of the tumor microenvironment on immune cells and their participation in neoangiogenesis. They seek to apply this knowledge to develop novel therapies and vaccines for cancer.
Cellular adhesion is the means by which cells bind to other cells or matrix proteins to form tissues and/or generate motion. At the molecular level, the adhesion is mediated by glycoproteins and/or glycolipids that protrude from the cell surface and form bonds with complementary constructs present on other cells or in the extracellular matrix. An aggregate of these non-covalent bonds supports a force that allows the cell to remain stationary or can be used by the cell as a means of locomotion. Cell adhesion is germane to a host of pathological processes, including cancer and pathological inflammation (e.g., arthritis). The research of three faculty members at Ohio University is directly related to cell adhesion.
According to the American Cancer Society, one in four deaths in the United States is due to cancer. Identification of the molecular mediators of metastasis (the process by which cancer spreads through the body) is critical in the search for a cure, since five-year survival rates decline precipitously once a primary tumor has spread. The two main avenues of metastasis are through the vasculature and the lymphatics. Monica Burdick, associate professor of chemical and biomolecular engineering, and her group are focused on developing a mechanistic understanding of the effects of fluid flow (blood and lymph) on cellular interactions pertinent to the distant and regional spread of cancer. Through the combined use of established and novel techniques in both glycobiology and biomedical engineering, they aim to identify molecular markers for cancer spread through the vascular and lymphatic system, characterize the functional role of those molecules (particularly in cell-to-cell adhesion), and define the kinetic and chemical requirements for binding to those molecules.
One of the main functions of leukocytes (white blood cells) is to fight infection and repair damaged tissue. Leukocytes continuously pass through the vasculature on the lookout for problems. Once a problem is found, the leukocytes accumulate at the site and destroy the invading organism and/or assist with wound repair. While this function is necessary for the organism’s survival, in pathological inflammation the leukocytes accumulate where they are not needed, which can lead to tissue damage and disease progression. David F. J. Tees, associate professor of physics and astronomy, and his group are working to understand the biophysical mechanisms that govern leukocyte adhesion in the lungs during serious infection, when a significant number of leukocytes can get trapped in the lungs, leading to organ failure. Since a large number of the vessels of the lungs are smaller than the diameter of the leukocytes, the leukocyte undergoes significant deformation during transit through the lungs. The Tees lab uses micropipette aspiration to analyze the microrheology of leukocytes, which gives insight into their deformability. The biochemical adhesion that occurs between the leukocyte and the vessel wall may also play a role in the trapping. To gain insight into the biochemical adhesion, this group uses force probe microscopy to determine the force dependence of the bonds that mediate leukocyte adhesion. Finally, in collaboration with Douglas Goetz, professor of chemical and biomolecular engineering, the Tees group investigates the relationship between leukocyte deformation and biochemical adhesion.
Once key molecular mechanisms of pathological processes have been identified, a next step in finding a cure for a particular disease is the identification of small molecule effectors of the mechanism. "Medicinal chemistry" is what Stephen Bergmeier, professor of chemistry and biochemistry, calls the research done by his group; that is, the study of drug design, drug synthesis, and drug action. The Bergmeier group is working on the development of new synthetic organic methods involving aziridines, which are strained three-membered rings containing one nitrogen. Aziridines hold great promise for the synthesis of biologically active, nitrogen-containing compounds such as antibiotics and central nervous system effectors. The Bergmeier group is also examining the design and synthesis of selective antagonists of the nicotinic acetylcholine receptor. These antagonists could be developed as therapeutics for addiction (e.g., smoking). Recently, Bergmeier and other faculty from the College of Arts and Sciences, the Russ College of Engineering and Technology, the College of Osteopathic Medicine, and the College of Health and Human Services teamed up on an internal grant to support enhancement of biotechnology infrastructure and personnel. A portion of these funds was used for a combinatorial chemistry facility that was established by Bergmeier and is now headed by him.
The development and utilization of antibiotics has saved millions of lives. Unfortunately, the widespread use of antibiotics has led to strains of bacteria that are resistant to a spectrum of commonly used antibiotics. Jennifer Hines, professor of chemistry and biochemistry, and her group are involved in a relatively new field of study: RNA-targeted drug design. RNA is important in bacterial regulation, as well as viral replication, and cancer biogenesis. The Hines group studies the structure-function relationships of novel RNA targets and the structure-activity relationship of medicinal agents that target the RNA. This work gives important insight into the factors that govern molecular recognition of RNA by small molecules. As a complement to their experimental work, the Hines group uses computational and bioinformatic approaches to create informational databases that can ultimately be used in the rapid drug screening of combinatorial libraries by NMR or in ribonomic studies of RNA arrays. This work provides a guide to the development of novel therapeutics. Recently, Hines and Stephen Bergmeier, professor of chemistry and biochemistry, identified a small molecule inhibitor that has great potential as a treatment for infections due to antibiotic-resistant bacteria.
Most microorganisms live in biofilm consortia that provide them with mechanisms that resist harsh environmental conditions including pH and temperature swings and antimicrobial agents. Some biofilms cause fouling and localized corrosion against metals such as stainless steel and other materials used as medical implants. Tingyue Gu, professor of chemical and biomolecular engineering, is interested in biocorrosion mechanisms, mass transfer in biofilms, bio-electrochemistry, and biofilm mitigation