Howard A. Young was born on January 29, 1948 in Ossining, New York. He
received a B.S. (magna cum laude) in Microbiology from the University of
Massachusetts in 1969. At the University of Massachusetts, he was elected
into the academic honor societies Phi Eta Sigma, Phi Kappa Phi and Phi Beta
Kappa. He did undergraduate research in the laboratory of Dr. Charles D. Cox
where he studied the growth characteristics of Leptospira sp. He
entered the doctoral program in Microbiology at the University of Washington in 1969 and
received an NIH predoctoral fellowship for his studies. He obtained his Ph.D.
from the Department of Microbiology, University of Washington in 1974. During
his thesis work under Dr. Helen R. Whiteley, he characterized and purified the
RNA polymerases from the dimorphic fungus, Mucor rouxii and
demonstrated changes in enzyme levels during the switch from yeast-like to filamentous
morphology. Following completion of his thesis, he was awarded an American
Cancer Society postdoctoral fellowship to study at the National Cancer
Institute with Dr. Edward Scolnick. During his postdoctoral fellowship, he
demonstrated that the rapid induction of mouse mammary tumor virus RNA by
glucocorticoids occurred through specific receptors. In addition, he was a
co-author on the manuscripts which reported the cloning of the H-ras and K-ras
oncogenes and he demonstrated that two independently derived transforming
viruses, Harvey sarcoma virus and the Rasheed rat sarcoma virus, contained the
same transforming gene. After his postdoctoral fellowship, he spent two years
at the Frederick Cancer Research Center as a Senior Scientist where he
continued his studies on the rat sarcoma virus. He then spent two years as
Head of Technical Services, Bethesda Research Laboratories. He joined the
Biological Response Modifiers Program, National Cancer Institute in 1983 as a
Cancer Expert in the Laboratory of Molecular Immunoregulation and in 1989
became Head, Cellular and Molecular Immunology Section, Laboratory of
Experimental Immunology. His major studies have focused in three related
areas: 1) the molecular regulation of IFN-gamma gene expression in NK and T
cells, 2) the consequences of aberrant IFN-gamma gene expression on immune
system development and maturation and 3) biochemical and molecular characterization of
lymphokine/cytokine gene activation by novel biological response modifiers.
He has served as an ad-hoc reviewer for numerous peer reviewed journals and is
currently on the Editorial Board of the Journal of Immunology, the Journal of Biological
Chemistry and the Journal of Interferon and Cytokine Research.
He has also participated in the grant and contract review process by
serving as an ad hoc member of several Source Evaluation Groups. He is
currently the Editor of the newsletter for the International Society of
Interferon and Cytokine Research and is on the membership committee of that
organization. In addition to that society, he is a member of the American
Association of Immunologists, the American Association for the Advancement of
Science, the Cytokine Society, the American Society for Microbiology and the
DNA Methylation Society. He has received an NIH Merit Award for his efforts
in support of the Werner Kirsten Student Intern Program. He is author or
co-author of over 130 scientific publications.
One experimental approach utilized to explore these questions has been the analysis of the role of DNA sequences in the control of IFN-gamma gene expression. This gene has been chosen because expression of IFN-gamma is largely restricted to two cell types, T cells and CD3- LGLs. Current work has continued to focus on identifying those regions of DNA that are involved in the response to various stimuli and the data indicates that there are multiple enhancer-like elements and at least two silencer elements in the human IFN genomic DNA. This tissue specific region, 5' to the coding sequence, contains both enhancer and silencer protein binding regions. Additional potential enhancer regions, are located in the first, second and third introns. We have identified specific nucleotide sequences that interact with DNA binding proteins for these regions. Our studies are also focused on identifying the biochemical signaling events that contribute to the IFN-gamma gene expression and determining if alterations in specific DNA binding proteins have occurred in these cell lines in response to treatment. As a second experimental approach, we have developed lines of transgenic mice which express IFN-gamma in the bone marrow. Analysis of the founder line indicates that these mice have a pronounced B cell deficiency as the bone marrow, spleen and lymph nodes lack both preB and mature B cells. Germinal centers are absent and both the spleen and bone marrow have a disrupted architecture. The animals also have reduced numbers of CFU-c and CFU-GEMM forming cells in the bone marrow. In addition, a decrease of CD4/CD8 double positive cells and an increase in single positive cells in the thymus is observed. Our data indicate that abnormal bone marrow expression of IFN-gamma results in alterations in many arms of the hematopoietic system and results in a severe B cell depletion. A third experimental approach towards understanding the regulation of cytokine/lymphokine gene expression has involved an analysis of the effects in vivo and in vitro of a chemotherapeutic drug, flavone-8-acetic-acid (FAA). Efforts within the CMIS have focused on a molecular analysis of the effects of FAA in vitro in order to elucidate the mechanisms by which it enhances cytokine gene expression and subsequent enhanced immune responsiveness to tumor challenge in mice but has failed in human clinical trials. A murine macrophage cell line has now been identified which expresses IFN-beta, MIP-1alpha, iNOS and IRF-1 mRNA in response to FAA. Efforts are concentrated on identifying the biochemical and molecular pathways involved in this gene induction and those regulatory regions of the specific cytokine genes that are required for enhanced gene expression in response to FAA in order to be able to FAA derivatives which may have therapeutic potential in human disease.
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Updated: July 1, 1996