The long-term goal of this project is to characterize the effects of a moderate period of suboptimal zinc on host defense systems and identify the underlying mechanisms causing the defects, using the mouse as a model system. Mononuclear phagocytes (MNP) from ZD mice were unable to take up or kill parasites unless preincubated with zinc. Experiments are proposed to examine the status of early reactions of the oxygen burst thought to be Zn-dependent as well as antigen processing and production of interleukin I, all of which are essential to host defense and may be defective. The density and distribution of cell surface proteins (FcR, CRIII, Iak, F4/80) that preliminary data indicate may also be altered in MNP from ZD mice will be quantitated to provide a more complete picture of the status of these cells. Conversely, lymphocytes from ZD mice showed no evidence of defects in function. Thus the reduced capacity of ZD mice to mount antibody and cell mediated responses appears to be related to the reduction in total numbers of lymphocytes observed throughout the peripheral immune system of the AZ mouse (lymphopenia). Therefore, failure of the bone marrow (BM) to produce adequate numbers of lymphocytes may represent the seminal event that causes the rapid demise of the immune system in ZD. Experiments are proposed to verify preliminary observations that ZD causes significant reductions in the total numbers of nucleated stem cells as well as Initially, proliferation and cycling of precursor cells in the bone marrow may be altered since Zn is critical to these processes. As Zn deficiency progresses, corticosterone (CS) is produced which is known to cause programmed death of immature thymocytes and may cause apoptosis of the immature, precursor lymphoid cells of the BM as well. Experiments are proposed to determine the role (s) of suboptimal Zn and CS in the suppression of lymphopoiesis associated with ZD in order to identify the underlying mechanisms causing lymphopenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052289-18
Application #
2430281
Study Section
Special Emphasis Panel (ZRG2-PSF (01))
Project Start
1996-06-01
Project End
1999-05-31
Budget Start
1997-06-01
Budget End
1998-05-31
Support Year
18
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Michigan State University
Department
Biochemistry
Type
Schools of Osteopathy
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Claycombe, Kate; King, Louis E; Fraker, Pamela J (2008) A role for leptin in sustaining lymphopoiesis and myelopoiesis. Proc Natl Acad Sci U S A 105:2017-21
Trottier, Mark D; Newsted, Matthew M; King, Louis E et al. (2008) Natural glucocorticoids induce expansion of all developmental stages of murine bone marrow granulocytes without inhibiting function. Proc Natl Acad Sci U S A 105:2028-33
Mann, J J; Fraker, P J (2005) Zinc pyrithione induces apoptosis and increases expression of Bim. Apoptosis 10:369-79
King, Louis E; Frentzel, Joseph W; Mann, James J et al. (2005) Chronic zinc deficiency in mice disrupted T cell lymphopoiesis and erythropoiesis while B cell lymphopoiesis and myelopoiesis were maintained. J Am Coll Nutr 24:494-502
Fraker, Pamela J (2005) Roles for cell death in zinc deficiency. J Nutr 135:359-62
Fraker, P J; Lill-Elghanian, D A (2004) The many roles of apoptosis in immunity as modified by aging and nutritional status. J Nutr Health Aging 8:56-63
Huang, Zhixin L; Fraker, Pamela J (2003) Chronic consumption of a moderately low protein diet does not alter hematopoietic processes in young adult mice. J Nutr 133:1403-8
Laakko, Tonya; Schwartz, Richard C; Fraker, Pamela J (2002) IL-7-mediated protection of pro and pre-B cells from the adverse effects of corticosterone. Cell Immunol 220:39-50
Lill-Elghanian, Deborah; Schwartz, Kenneth; King, Louis et al. (2002) Glucocorticoid-induced apoptosis in early B cells from human bone marrow. Exp Biol Med (Maywood) 227:763-70
King, Louis E; Fraker, Pamela J (2002) Zinc deficiency in mice alters myelopoiesis and hematopoiesis. J Nutr 132:3301-7

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