Pamela J. Fraker
Professor
- Member, National Academy of Sciences
- B.A. 1966, Purdue University
- Ph.D. 1971, University of Illinois
- Postdoctoral Associate 1971-73, University of Illinois Medical Center
- Young Investigator Award, 1981, American Institute of Nutrition
- Goldsmith Research Award, 1993
- Distinguished Faculty Award, 1998, Michigan State University
fraker@msu.edu
419 Biochemistry Building
Michigan State University
East Lansing, MI 48824-1319
Office: 517-353-3513
Lab: 517-353-9585
FAX: 517-353-9334
Lab Home Page
FASEB 2007 Summer Conference
"Nutrition Immunology"
Publication search:
Pamela J. Fraker Research Interests continued
Apoptosis (Programmed Cell Death) - continued
Thus, understanding how apoptosis is
initiated and/or prevented is of great importance. Glucocorticoids are one
of the prime inducers of apoptosis among cells of the immune system. Our
lab was among the first to show that malnutrition, e.g., suboptimal
dietary zinc or protein-calorie intake causes chronic production of
glucocorticoids which, in turn, initiates apoptosis in young developing B
and T-cells.
Further studies
are in progress to determine effect of glucocorticoid produced during malnutrition, trauma, stress, etc., on lymphopoiesis (production of lymphocytes)
to include its effects on cell cycle status, rates of apoptosis, gene
rearrangement, cytokine production, etc. More recently, we also discovered that
nanomoles of free zinc can induce apoptosis in a variety of kinds of cells.
Release of zinc within cells appears to play a role in neurological damage and
may play a role in other situations where cells are under stress. Studies are in
progress to determine how zinc initiates a death signal and whether or not
Ca++ release, caspases, lipid inversion and oncogenes such as bcl-2
are a part of the zinc death cascade.
Nutritional - Immunology - continued
This leads to enhanced rates of infection and mortality. Zinc deficiency is a component of the aforemention diseases and a frequent dietary deficiency noted in the human population. For this reason our studies have primarily utilized the zinc deficient mouse as a model for study. We have recently shown that the lymphopenia that accompanies many forms of malnutrition is caused by disruption of lymphopoiesis.
The latter is caused by heightened levels of apoptosis among precursor T and B-cells that is mediated by the chronic production of glucocorticoids induced during zinc deficiency, protein-calorie malnutrition, wasting, etc. Studies are in progress to determine the effect of suboptimal nutriture in the rate of lymphopoiesis, status of pro and precursor lymphocytes, rates of apoptosis, cell cycle status, cytokine production, etc., using flow cytometry as the primary assessment tool.
Of additional interest is the recent discovery of an important adaptive response to malnutrition. It now appears that the first line of immune defense - the phagocytic cells may be protected during stress-malnutrition. Both the peripheral blood and the marrow of zinc deficient mice contained enhanced numbers of these cells. Interesting human neutrophils exposed to levels of glucocorticoids analogous to those found in malnourished subjects have longer half-lives and greater resistance to apoptosis! Studies are in progress to further define this important observation to include biochemical evaluation of the changes in neutrophils, etc., that make them more resistant to apoptosis during nutritional deficiencies. Protocols for measuring cell cycle status, apoptosis, ploidy, receptor expression, oncogene expression, Ca++ flux, mitochondrial status, phenotypic distribution of leukocytes, etc., are routinely performed. Opportunities exist for students to learn flow cytometry which is an important and highly marketable skill.
Stress - Survival Responses of Neutrophils - continued
Joe Frentzel in our lab has shown that within 30 minutes of exposure of human neutrophils to Gc the majority of the ligand bound Gc receptors move from the cytosol into the nucleus. This event would predict major changes in gene expression. Indeed there is a four to ten fold increase in mRNA and protein expression for G1LZ . Interestingly GILZ is a so call Gc-induced leucine zipper protein that has been shown to modulate transcriptional activity in a way that can promote survival. Although a battery of Bcl-2 members that have anti-apoptotic capacity were also analyzed, no significant changes in these proteins were noted. Experiments are in progress better define the protective role of G1LZ . We also hope to identify other novel neutrophil survival genes as well as determine the functional capacity of neutrophils exposed to Gc and other natural stresses.
FLOW CYTOMETRY - continued
Protocols for measuring cell cycle status, apoptosis, ploidy, receptor expression, oncogene expression, Ca++ flux, mitochondrial status,
phenotypic distribution of leukocytes, etc., are routinely performed.
Opportunities exist for students to learn flow cytometry which is an important
and highly marketable skill.