This application describes a 5-year training program for the development of a career in academic medicine. This application will allow the candidate to acquire extensive training in the area of reproductive and molecular biology and medicine through a unique integration of resources of the Wisconsin Primate Research Center and the Department of Pathology, and to address the research plan outlined below. This program will focus on the mechanisms of interaction of trophoblasts with uterine macrophages using rhesus monkey as a model. Dr. Golos, Associate Professor, Department of Obstetrics and Gynecology will mentor the Principal Investigator's performance. He is a recognized leader in the field of primate reproductive biology. To enhance the training, the program will include Dr. Malter, Professor of Pathology, as co-mentor and an expert in the molecular biology of cytokine expression. In addition, an advisory committee of highly regarded senior medical scientists will provide scientific and career advice. In this application, my central research hypothesis is that the interaction of decidual macrophages with extravillous trophoblasts can be mediated through interaction of the non-classical MHC class I molecule Mamu-AG, expressed on rhesus trophoblasts, with immunoglobulin-like transcript (ILT) receptors, expressed on macrophages. To test the hypothesis that the non-classical MHC class I molecule Mamu-AG can protect invading cytotrophoblasts from killing by macrophages through interaction with ILT2 and ILT4 receptors, I will address the following specific aims: 1) To characterize the distribution and immunophenotypes of rhesus monkey decidual macrophages and to develop successful methods for their isolation; 2) To clone ILT2 and ILT4 receptors from the rhesus monkey decidua, to produce soluble rhesus monkey ILT proteins and to produce monoclonal antibodies (mAbs) against these proteins; and 3) To assess whether Mamu-AG protects targets from killing by decidual macrophages through interactions with ILT2 and ILT4. The accomplishment of this plan will facilitate the candidate's transition to a career as an independent scientist, provide the candidate with a novel expertise in non-human primate reproductive physiology, and establish the basis for the development of an independent state-of-the art research program in molecular mechanisms of pregnancy pathology in humans and using experimental primate models.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD044067-02
Application #
6711718
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Hewitt, Tyl
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$91,800
Indirect Cost
Name
University of Wisconsin Madison
Department
Pathology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Salvagiotto, Giorgia; Zhao, Yun; Vodyanik, Maxim et al. (2008) Molecular profiling reveals similarities and differences between primitive subsets of hematopoietic cells generated in vitro from human embryonic stem cells and in vivo during embryogenesis. Exp Hematol 36:1377-89
Metallo, Christian M; Vodyanik, Maxim A; de Pablo, Juan J et al. (2008) The response of human embryonic stem cell-derived endothelial cells to shear stress. Biotechnol Bioeng 100:830-7
Slukvin, I I; Grendell, R L; Rao, D S et al. (2006) Cloning of rhesus monkey LILRs. Tissue Antigens 67:331-7
Slukvin, Igor I; Vodyanik, Maxim A; Thomson, James A et al. (2006) Directed differentiation of human embryonic stem cells into functional dendritic cells through the myeloid pathway. J Immunol 176:2924-32
Golos, Thaddeus G; Bondarenko, Gennadiy I; Breburda, Edith E et al. (2006) Immune and trophoblast cells at the rhesus monkey maternal-fetal interface. Methods Mol Med 122:93-108
Breburda, E E; Dambaeva, S V; Slukvin, I I et al. (2006) Selective distribution and pregnancy-specific expression of DC-SIGN at the maternal-fetal interface in the rhesus macaque: DC-SIGN is a putative marker of the recognition of pregnancy. Placenta 27:11-21
Vodyanik, Maxim A; Thomson, James A; Slukvin, Igor I (2006) Leukosialin (CD43) defines hematopoietic progenitors in human embryonic stem cell differentiation cultures. Blood 108:2095-105