Research Spotlight > Archives
Dr. Nathan Shankar in his lab. Nathan Shankar, Ph.D.
Associate Professor of Pharmaceutical Sciences
Department of Pharmaceutical Sciences
The increasing incidence of antibiotic resistance has brought a new sense of urgency to the discovery and development of antibacterial drugs. For over a decade Shankar has been actively involved in research areas such as microbial pathogenesis, antibiotic resistance, and anti-infectives. Phrases like "enterococcal virulence" and "antibiotic resistance" are always on the scientific minds of Dr. Nathan Shankar and his research personnel.
Effectively conquering antibiotic resistance will require expanding available targets. One approach to this problem is to identify new targets by panning the genomes of antibiotic resistant bacteria. Enterococci, Gram-positive bacteria normally growing as commensal organisms of the gut, have emerged as a leading cause of nosocomial (hospital-acquired) infections and are frequently resistant to multiple antibiotics.
Although the ability of Enterococcus faecalis to cause serious disease is well recognized, not much is known about enterococcal virulence factors that contribute to pathogenesis. For instance, factors which may influence the ability of enterococci to colonize host tissues, translocate across epithelial barriers, or survive in grossly different host environments are poorly understood. His laboratory is interested in the identification of potential virulence determinants in E. faecalis that play a role in enterococcal pathogenesis, with particular emphasis on enterococcal surface components. The lab’s long term interest is in the development of novel therapeutic approaches to treat serious enterococcal infections by targeting bacterial components that aid the bacteria in causing disease.
According to Dr. Shankar, associate professor within the department of pharmaceutical sciences, his research involves the following current projects:
Dr. Nathan Shankar and assistant Arto Baghdayan. - Biofilm formation by E. faecalis – Enterococci can adhere to abiotic surfaces like catheters and instrument surfaces in the hospital setting, persist over long periods of time and thus cause serious infections in the compromised host. Our laboratory has made some important discoveries trying to understand the role of a specific bacterial surface protein called Esp, that mediates adhesion to abiotic surfaces. We are currently examining the structure-function relationship of this protein and working at dissecting out the minimal region of this protein that is sufficient to enable adhesion. This information could potentially drive the development of a small molecule inhibitor to prevent enterococcal biofilms and infections.
- Genome plasticity and diversity in Enterococcus – The genus Enterococcus is equipped with a number of mechanisms to exchange genetic material. Diversity among strains is generated by horizontal transfer of transposons and plasmids which often encode antibiotic-resistance markers and virulence factors. Our laboratory recently identified the first pathogenicity island, which is a large cluster of virulence genes in the genome of pathogenic strains, in E. faecalis. We also showed for the first time how the pathogenicity island or parts thereof, can disseminate to other strains resulting in the creation of more virulent strains.
- Pilus biogenesis in Enterococcus - A fairly new project in our laboratory is examining the roles of novel genes within a unique gene locus termed the bee locus for biofilm enhancer in enterococcus. This locus encodes a pilus, which is a long hair-like projection at the cell surface, and such surface appendages are known to be important adhesins facilitating bacterial colonization of host tissues. We are examining the expression of these proteins, their distribution at the cell surface and role in interaction with host cells.
- Host-pathogen interactions - Our most recent work has focused on host-pathogen interactions during enterococcal infection. In addition to examining bacterial factors which might influence colonization of the host gut (in collaboration with Dr. Mark Huycke at the VA Hospital), we are interested in understanding how the bacterium evades host immune defenses once an infection occurs. In this regard we have identified a new transcriptional regulator in E. faecalis which enables this bacterium to overcome rapid clearance by macrophages. Persistence within macrophages results in systemic infection and significantly compromises host health. We are also currently examining the interaction of enterococci with dendritic cells in collaboration with Dr. Shanjana Awasthi in the department. Our laboratory is also involved in collaborative studies with investigators (Drs. Robert Hurst and Ricardo Saban) in the departments of urology and physiology, respectively, at OUHSC to study host responses to enterococcal infection of the urinary tract.
Research Assistant Arto Baghdayan. 
Dr. Tracy Hagemann at the 2008 YMCA immunization drive. Tracy M. Hagemann, Pharm.D.
Associate Professor
Department of Pharmacy: Clinical and Administrative Sciences
Dr. Tracy Hagemann has been with the College of Pharmacy for 12 years and currently serves as an Associate Professor in the Oklahoma City Department of Pharmacy: Clinical and Administrative Sciences. For over a decade, she has been actively involved in pediatric oncology – both in supportive care and research. When asked about changes she has observed in regard to pediatric oncology therapy over the years, Dr. Hagemannn stated that the increase in survival curves, more accurate diagnoses, better supportive care, and the development of better antinausea medications represent the most significant advances in therapy. According to Dr. Hagemann, one of the biggest challenges in dealing with the pediatric population is having health care professionals recognize the fact that children are not just little adults; their bodies work and metabolize differently.
Of particular interest to Dr. Hagemann is complementary and alternative medicine (CAM). CAM involves therapeutic agents such as herbal medicine, prayer, and yoga. At present, she is conducting a project titled: “Survey of the Prevalence of Use of Complementary and Alternative Medicines in a Pediatric Outpatient Population.” The project is in its second year and patient enrollment is almost complete. Patients participate in an interview that consists of questions regarding their attitudes and their guardians’ perceptions regarding the frequency of use, effectiveness, and belief in potential benefits of CAM therapeutic agents.
Dr. Hagemann is also working with a Pharm.D./MS student on another project “A Retrospective Investigation of Prolonged Methotrexate Clearance in Children.” Methotrexate (MTX) is a component of the standard treatment for certain leukemias and bone cancers in the Children’s Oncology Group (COG) protocols. The overall question that is being addressed by this study is why some pediatric patients can exhibit variations in how fast they clear MTX. This phenomenon apparently has a genetic component; however, the same individual patient will clear MTX quickly on one occasion, then slowly on another. The research design of this study will examine differences between groups of patients and differences at specific time points within the same individual patient. The data for the project have been collected and analyses will be completed by the end of next summer.
Another research area Dr. Hagemann is pursuing is the assessment of effective dosing in obese children. The title of this pilot study is “Evaluation of Medication Dosing in Overweight Children.” For this project ‘overweight’ is defined as having a body mass index (BMI) of ≥ to the 85th percentile on the pediatric BMI scale. (The pediatric BMI scale is interpreted differently; a BMI of ≥ to the 90th percentile is considered obese). Dr. Hagemann estimates that 34% of her patient population qualifies as overweight using these standards. At present, there is a void in the literature regarding what is a safe and effective dose for an overweight child given a specific weight/age. The solution is not as simple as giving an adult dosage of medication to an overweight child even if that child weighs the same as an adult because a child’s chemistry and therefore, their metabolism, is different. The issue of safety and effectiveness becomes especially important when antibiotics and analgesics are involved. The ultimate goal would be to develop clinical markers that would inform physicians that more doses and/or more increased doses are necessary given a particular characteristic of a child.
Mark Stratton, Pharm.D., BCPS, GCP, FASHP
Geriatrics
Dr. Mark Stratton joined the College of Pharmacy in 2001 as Professor and Herbert and Dorothy Langsam Endowed Chair in Geriatric Pharmacy. His main research interests are in geriatric pharmacotherapies with a particular emphasis on seniors over the age of 75 years. Recent funding for Dr. Stratton included a Presbyterian Health Foundation grant entitled: “Analysis of Treatment for Hyperlipidemia in the Old-Old.” Dr. Stratton authored an article “Disparities in the Prevalence of Medication Therapy for Hyperlipidemia in the Elderly” that covered the results of this research and the article was published in The Consultant Pharmacist volume 22 number 10 October 2007.
The leading cause of death in people 75 years of age and older is atherosclerotic coronary artery disease (CAD). Dr. Stratton states that this demographic population is under-represented in research pertaining to CAD as well as most other cardiovascular diseases. His research regarding hyperlipidemia has shown that older people were prescribed therapy less frequently than younger people, that women were prescribed therapy less frequently than men, that Caucasians were prescribed therapy more frequently than African-Americans, and that those living in a nursing facility were prescribed therapy less frequently than those living in other settings. Dr. Stratton also feels that while these differences in rates of therapy were statistically significant, more research needs to be done before the results can translate to a meaningful clinically significant phenomenon.
He is also actively securing funding for the development of a program to evaluate the impact of clinical pharmacists who would provide medication therapy management for home bound elders.
Dr. Stratton is the 2008 recipient of the American Society of Consultant Pharmacists (ASCP) Leadership in Education Award. This award recognizes the unique and innovative educational endeavors of ASCP members. Dr. Stratton will be presented with the award by the ASCP Midyear Conference in May 2008.
Dr. Kelly StandiferKelly Standifer, Ph.D.
Wound Healing
Dr. Kelly Standifer joined the College of Pharmacy as Professor of Pharmaceutical Sciences. Her research interests, ultimately, is to develop alternative therapeutic options (to morphine) for the treatment of severe pain. The newest member of the opioid receptor family, opioid receptor like-1 receptor (ORL1), and its endogenous agonist, orphanin FQ/nociceptin (OFQ/N), have been strongly implicated in the development of morphine tolerance. Chronic morphine treatment increases levels of OFQ/N; blocking the actions of OFQ/N significantly reduce the extent to which the analgesic actions of morphine are reduced. Using human neuronal cell lines that natively express mu and ORL1 receptors, we study the cellular mechanisms of ORL1 and mu opioid receptor activation (by the endogenous peptides OFQ/N and Dynorphin, and the synthetic agonists, DAMGO and morphine), and the cellular mechanisms of ORL1- and mu opioid receptor-mediated mu and ORL1 tolerance and cross-tolerance. Acutely, OFQ/N activates protein kinase C (PKC), which activates and translocates G protein-coupled receptor kinase 2 (GRK2) and GRK3 to the cell membrane where GRK2 can quickly desensitize the mu opioid receptor in the presence of a mu opioid agonist such as morphine. Our next step is to determine where these changes occur in vivo, and how they might be manipulated to reduce the extent of morphine tolerance development.
ORL1 desensitization is produced by GRK3. Tolerance induced by prolonged exposure to OFQ/N and/or morphine treatment also involves GRK. Similar to morphine, prolonged OFQ/N treatment (24 h or more) upregulates GRK levels. Ultimately, though, it is the increased availability of GRK that produces the rapid tolerance and/or cross-tolerance upon challenge with an agonist. We are in the process of studying ORL1 phosphorylation sites, and how mutation of these sites affects receptor function.
Randle Gallucci
Liver Damage
Dr. Randle Gallucci recently received an RO3 award from the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIAAA, NIH). The two year award is $100,000 in direct costs and will be active from April 1, 2006 through March 31, 2008. The name of the research is "Gender Differences in Liver IL-6R Expression."
An R03 is considered a small grant award mechanism. It is designed for very targeted areas of research which can be accomplished with a restricted budget in a smaller timeframe.
When asked about this research, Dr. Gallucci explained that his laboratory is investigating why women have worse alcoholic liver disease as compared to men. It looks like it has something to do with increased inflammation in the liver. The lab has found a specific inflammatory gene (interleukin 6 receptor) is increased in the livers of alcohol consuming female rats as compared to males. He hopes to find out why this gene is upregulated in females, and perhaps manipulate its function to see if that will decrease alcoholic liver damage.
Dr. Gallucci also has an RO1 award from the National Institute of General Medical Sciences, National Institutes of Health (NIGMS, NIH) entitled, "Identification of an IL-6 induced keratinocyte motogen." This project deals with the role of inflammation in skin wound healing. The point of the project to find out how a specific inflammatory gene is aiding healing, and through its manipulation help patients with chronic ulcers. This is a five year award, and this past year May 1, 2005 through April 30, 2006 marked the third year of this research.
Thomas Pento
Breast Cancer
Cancer has been the focus of Dr. Tom Pento’s research for the past 20 years. Dr. Pento, a pharmacy professor at the College of Pharmacy, and a leading researcher at the OU Cancer Center, said scientists will not beat cancer with one drug or one treatment, but will soon succeed in producing medicines that will stop the disease that affects nearly half of all men and a little over one third of all women in the United States in their lifetimes.
Working with Dr. Xiao-Ping Zang, Pento’s lab is exploring Keratinocyte Growth Factor (KGF), an element produced in the supportive tissue around the tumor. KGF speeds the growth and migration of cancer cells.
In other research, Dr. Pento is working with Dr. Roger Harrison, an OU chemical engineering professor, to develop a protein compound that would deprive a cancer cell of a specific protein it needs to spread. They have applied for a patent on their work and hope to turn it into a viable treatment in 10-15 years.