Delaware Biotechnology Institute

Head of Molecular Genetics,
Cellular and Tissue Transplantation and
Director of Structural and Functional Genomics Diagnostics
Nemours Biomedical Research

Alfred I duPont Hospital for Children
1600 Rockland Road
Wilmington, DE 19803

Phone: (302) 651-5778
FAX: (302) 651-6888
Email: lkrueger@nemours.org
Web site: http://www.udel.edu/bio/nemours/people/lkrueger.html

Education:
Postdoctoral, Rockefeller University
Postdoctoral, National Heart, Lung and Blood Institute
Ph.D., Johns Hopkins University
M.S., Johns Hopkins University
B.S., Rutgers - The State University of New Jersey

Research Interests:
The investigative goal of the Molecular Genetics, Cellular and Tissue Transplantation is to identify and to intervene in the mechanisms that result in increased morbidity and mortality in patients suffering from posttransplant disorders (PTLD). The focus of Structural & Functional Genomics Diagnostics is to provide state-of-the-art diagnostics for the transplant team and their patients.

While transplantation is a life saving, curative and sustaining procedure, a small population of these children faces complications related to the lifelong requirement for immunosuppression. Using sophisticated genetic and proteomic technologies, we provide in concert with Stephen P. Dunn, M.D., Chief, Section of General Pediatric Surgery and Section of Solid Organ Transplantation and his staff, direct investigation into the complex mechanisms unique to the transplant population. We are currently focusing on a drug that affects an evolutionarily conserved, universal metabolic pathway, the mTOR pathway. We are trying to extend the use of the drug from an immunosuppressant to an anti-lymphomagenic drug for PTLD. Other interests include targeted intervention in oncogene function. Finally, because of the impact of surgery in transplantation, we have recently fostered an interest in bleeding and clotting disorders. Additional cancer projects examine the role of integrating global DNA microarray and the intermediate Luminex technologies for microRNA analyses to the more sensitive, but limited, real-time PCR (see below).

Additionally, this evolutionary conservation of the antiproliferation effects of rapamycin allows us to examine the drug in breast cancer. Genetic and functional heterogeneity within the breast cancer population impairs therapeutic intervention, facilitates tumor resistance and can ultimately lead to therapeutic failure. A single malignant breast cancer cell can be represented as an interactome (map of the complex protein-protein actions) that constitutes the ability of a cell to grow, adapt, respond and die. The evolving neoplastic cell also interacts with normal surrounding local stromal cells, cellular and tissue elements. The result of these diverse processes makes breast cancer cells robust and resilient. Each change from the original clone represents a potential additional therapeutic complication. Because mTOR inhibitors can dominantly stop growth in the presence of growth factors and are well defined with effects that are relatively non-toxic, it becomes a primary core drug for new anti-cancer approaches. The overall goal is the identification of gene products and their pathways that enhance the response to this treatment. The inhibition of the mTOR pathway results in antiangiogenic, direct antineoplastic, pro-apoptotic and growth modulating effects. However, much work remains in understanding the mechanism of action of the mTOR signal. We are currently examining the role of other genes that affect the cellular response to mTOR inhibition in vitro. In xenograft transplants into animal models, siRNA-expressing vectors will be used to target specific mRNAs. These efforts are enhanced by a long-standing multi-institutional alliance between Patricia Soteropoulos, Center for Applied Genomics (CAG); Christiana Care Health Systems through the auspices of Brian W. Little, M.D., Ph.D., Vice President for Academic Affairs and Research; the Delaware Biotechnology Institute (DBI) and with Nicholas J. Petrelli, M.D., Medical Director, Helen F. Graham Cancer Center.

In the Structural and Functional Genomics Core the clinical service is expanding greatly as it progresses from a specialized service for the pediatric transplant community to a central and more general molecular diagnostic service of the hospital. Our molecular diagnostic goal is to develop and initiate "homebrew" diagnostics that are available real time to the medical community. In Structural and Functional Genomics Diagnostics, we have expanded the clinical service from a specialized service for the pediatric transplant community to a central and more general molecular diagnostic service of the hospital. Because our primary goal remains providing state-of-the-art research into the areas that enhance the positive benefits of liver transplantation, we have an extensive educational program that is both translational and basic in scope. These experiences include fellow, resident, postdoctoral and undergraduate projects and are central to our mission.