Barry J Margulies, PhD - US grants

DESCRIPTION (provided by applicant): Herpesviruses are infectious agents found worldwide throughout the human population. A paradigmatic member of this family, herpes simplex virus-1 (HSV-1), causes recurrent cold sores and fever blisters. As a member of the herpesviruses, HSV-1 resides within the host for life in a quiescent state called latency. However, latent HSV-1 can reappear at any time, causing potentially debilitating disease. Current therapies for long-term management in patients who are infected with HSV-1 are primarily based on daily multiple oral dosing of nucleoside analogues, such as acyclovir (ACV) or valacyclovir (Valtrex(R)). These therapeutic regimens, though, are not ideal;they require a high degree of patient compliance to maintain suppressive levels of the drug because low quantities of drug are absorbed from the gastrointestinal drug, and the drug that is absorbed is rapidly cleared by the kidneys. Furthermore, poor patient compliance can lead to periods of active HSV-1 replication that may result in the appearance of ACV-resistant mutants. A better option for these patients would be a single administration of ACV that could last for the long-term, even years. ACV has therefore been combined into a silicone implant that releases suppressive levels of the drug in a controlled manner, with near zero-order kinetics, over the course of at least two months. This intervention can theoretically last for 3-5 years. These implants prevent primary infection of HSV-1 in vitro and recurrent infection in vivo, and have broader applicability with proven in vitro efficacy of a similar antiherpetic, penciclovir, in place of ACV. The experiments proposed in this grant application are geared towards better implementation of these silicone implants for eventual utility in a clinical setting. First, engineering of these implants will continuously be improved by altering geometry, polymer, drug, and drug percent load to establish better and more effective drug release kinetics. Second, relative efficacy in preventing recurrent episodes of HSV-1 reactivation will be explored in the murine model. Both longer term suppression, over nine months, and the utility of improved implants design, will be examined. All of these experiments should lead to improved implementation of these silicone-ACV implants. In the distant future, we would expect that such long-term continuous ACV delivery could lead to clinical trials, where they may prevent HSV-1-induced disease for years with a single implantation. PUBLIC HEALTH RELEVANCE: HSV-1, the etiologic agent of cold sores, fever blisters, and potentially life-threatening complications in especially immunocompromised patients, is normally present in 60-80% of the American population. Research in long-term, single implantation therapies with silicone-acyclovir controlled release devices may prevent reactivations of the virus, relieving patients of the need for multiple oral daily doses of these drugs and preventing the potential appearance of drug-resistant strains of the virus. Additional research, proposed herein, is required for continued biological, chemical, and pharmacological characterization of these implants, looking towards ultimate development of this strategy to make a significant impact on HSV-1-induced disease.

With this award from the Major Research Instrumentation (MRI) and Chemistry Research Instrumentation and Facilities (CRIF) programs, Towson University will acquire a liquid chromatography-mass spectrometry (LC-MS) system. The system will be used to analyze the composition of complex materials obtained from various sources including samples from environmental sources, chemical reactions or biological origins. In this system, the liquid chromatograph (LC) separates the mixture into its individual components. Then the mass spectrometer (MS) ionizes the components and determines their mass by measuring the mass to charge ratio (m/z) of the ions. This is a widely used analytical tool to identify what is the composition of a mixture or material. The instrument will be used by students in their research, training them with sophisticated, modern instrumentation. Students in laboratory courses will be trained to use it including students in the only BS Forensic Chemistry program in Maryland.

The award will be used in research projects, such as (a) investigating the formation of disinfection by-products in drinking water resulting from reactions between so-called inert constituents of herbicide formulations and chemical disinfectants; (b) analyzing chemical composition of atmospheric aerosols; (c) improving polymer-based controlled-release technology for anti-herpetic drugs; and (d) improving traceability of cocoa through chemometric analysis of chemical signatures.

Summary A talented and diverse biomedical workforce is essential to ensure creativity and innovation in the biomedical field. The goal of this project is to promote growth and maintenance of a diverse biomedical workforce by increasing the number of underrepresented minority (URM) students who pursue biomedical careers. While URM students are as likely as others to begin college as STEM majors, they are less likely to graduate with a STEM degree. The attrition of students from STEM majors is acutely seen in students who begin college at two-year institutions (many of whom are URM students) than at four-year institutions. Consistent with these trends, 48% of Towson University (TU) natural science majors enrolled in introductory chemistry were found to have completed a bachelor?s degree in the natural sciences within 5 years; this percentage dropped to 41% for transfer students. This project targets the transition of URM students from Baltimore City Community College (BCCC) and the Community College of Baltimore County (CCBC) to facilitate baccalaureate degree completion in the biomedical sciences at TU or other four-year institutions and to increase student competitiveness for graduate education and/or biomedical research careers. This renewal proposal builds on past success and implements new strategies to empower and motivate participating students. We aim to enhance recruitment efforts to increase program awareness and the pool of qualified applicants attracted to the program, to provide a dynamic and supportive environment for students to increase the transfer rate of students from our community college partners to TU and other four-year institutions, to provide students with the skills and capacity required for success at TU and in post-graduate training and careers, and to integrate the program with the robust pipeline of active URM training programs at TU, BCCC, CCBC and affiliated University System of Maryland schools to provide a strong minority-focused training experience. These goals will be achieved by integrating an independent research experience with strong mentoring and courses for research and professional skills development along with fostering the development of research-based curriculum at the community college partners. Building on previous success, the new initiatives proposed here include strengthening research opportunities at the community college partners to better prepare students for the research experience at TU by fostering the development of course-based undergraduate research experience (CURE) modules at the community college partners, and strengthening the integration of the Bridges to the Baccalaureate program with other minority- focused programs at partner institutions and within the University System of Maryland.