James Morrison - US grants

minority institution research support; secondary schools;

biomedical equipment purchase;

The marine natural product, bryostatin, is in Phase II clinical trials in Britain for the treatment of cancer. The very low natural abundance of this class of compounds, a few parts per billion to several hundred parts per billion, and a lengthy synthesis of one member may hinder wider clinical studies. Bryostatins wide variety of biological effects is traced to binding to PKC(protein kinase C). The size and complexity of PKC precludes detailed investigation of its phorbol ester/diacylglycerol binding domain by X-ray crystallography or NMR. Smaller peptides (approximately 50 residues) which incorporate this subdomain can be studied by NMR. The binding of bryostatin to these peptides will be quantified using [26-3H]-bryostatin and qualitatively by NMR using 13C, 15N labeled peptides. As a medium resolution structure of one of these peptides is in hand, the determination of the exact structure of its bryostatin binding domain is a reasonable goal. Once the binding site is known, then the conformation of bryostatin in this site can be determined by 2-D NMR. Knowledge of this fit to the binding site will enable simplified analogs to be made which incorporate the features necessary for binding. Routes to potentially useful analogs are provided.

The National Toxicology Program (NTP) was established as a cooperative effort within the Public Health Service (PHS) of the Department of Health and Human Services (DHHS) to coordinate and manage toxicological research and testing activities within the Department, to provide scientific information on potentially hazardous chemicals to regulatory and research agencies, scientific and medical communities, and the public, and to strengthen the science base in toxicology. This interagency program comprises one of the world's largest scientific data resources for animal toxicity/carcinogenicity studies. The NTP consists of the relevant toxicological activities of the National Institute of Environmental Health Sciences, the National Institute for Occupational Safety and Health, the National Cancer Institute, and the National Center for Toxicological Research. Through its activities, the NTP provides either directly or indirectly, a large component of the basic scientific data that other Federal and State scientific and regulatory agencies as well as private sector organizations utilize in responding to issues relevant to the effects of chemicals on human health and the environment. Thus, the ultimate role of the NTP in the research and testing of chemicals and agents is the protection of health of the American public from exposure to hazardous chemicals.

This contract provides NIEHS/NTP with a wide variety of collaborative pathology services that best support NTP's evolving toxicologic research and chemical/agent testing mission. The services provided range from traditional GLP-compliant toxicologic pathology support and the conduct of the Pathology Working Groups to the development and/or refinement of special pathology-based procedures and innovative technologies responsive to investigative research concerns and mechanistic issues. Because the NTP's service needs are largely unpredictable, adequate numbers of NTP-qualified and experienced pathologists, proficient technical personnel and support staff must be committed on an as-needed basis to be immediately responsive to the collective pathology requirements of eight individual task assignments, including several involving client-site services.

The subject contract was established to provide a broad range of routine and specialized pathology services in support of studies conducted under contract by the National Toxicology Program (NTP) and for supplemental studies on pathology specimens generated through these studies. The contract also provides critical pathology (including molecular pathology) support for studies conducted by in-house investigators at NIEHS and other NIEHS contract studies. Specifically, the following services are supported by this contract: 1) necropsy and in-house necropsy assistance; 2) histology (tissue trimming and processing, slide preparation, and staining); 3) histopathological evaluation/interpretation; 4) application of specialized qualitative and quantitative morphological procedures (immunohistochemistry, morphometrics, cell proliferation, apoptosis, electron microscopy); 5) adaptation, development, refinement, application of new techniques in cellular and molecular biology including (but not limited to) genotyping, DNA sequencing, in situ hybridization, DNA and RNA isolation and amplification, and real time, quantitative, and in situ PCR, as well as training in the application of these techniques; 6) Pathology Peer Review (including Pathology Data Review [PDR], Audit of Pathology Specimens [APS], Quality Assessment of pathology evaluations and Pathology Working Group Coordination [QA/PWG]) and technical support for these activities; 7) pathology data entry; 8) presentation or publication of pathology data or techniques, or support for these activities; 9) on-site pathology support, and 10) administrative support for the laboratory animal medicine group. The following work was completed for the National Toxicology Program and the NIEHS on this contract in the past year: 1 QA/PWG review; 27 projects for preparation of histology slides, primary histopathological evaluations for 5 immunotoxicity studies, 9 special histopathological evaluation for NTP and NIEHS studies, 1 immunohistochemisty staining project, 3 projects for preparation of materials for publication in scientific journals, and on-site support in the NTP Laboratory Animal Group (1 Laboratory Animal Veterinarian and 1 administrative support staff), and in the NIEHS Core laboratories (2 technical support staff). In addition, there are several other projects for the NTP and NIEHS that are in progress.