This proposal aims to train the applicant to become an independent physician-scientist studying microchimerism and the treatment of inherited disorders. The application describes a 5 year mentored program to develop scientific expertise in microchimerism, stem cell biology, immune tolerance, and the treatment of inherited diseases. This will build on his training in glycobiology, biochemistry, molecular biology, and gene therapy. Dr. Mark Sands, a recognized leader in the study of lysosomal storage diseases, will mentor the PI's scientific career development. An advisory committee will provide additional scientific and career guidance. The research proposed will evaluate maternal-fetal microchimerism to determine what cells are necessary to produce and maintain chimerism, and will evaluate ways to enhance maternal-fetal microchimerism to provide therapy in a mouse model of Mucopolysaccharidosis VII. Preliminary data indicates maternal-fetal microchimerism can be increased with stem cell mobilizing or vascular permeabilizing agents. We hypothesize the microchimerism is increased by increasing circulating maternal stem cells and increasing placental permeability to maternal stem cells. We also hypothesize that by increasing microchimerism, the normally functioning maternal cells in the offspring could provide the missing enzyme to cross correct the offspring's deficiency. We will test these hypotheses with the following specific aims:
Specific Aim 1 : Determine if maternal-fetal microchimerism is affected by type and number of circulating cells in the mother 1A. Determine if increasing bone marrow cell number delivered to maternal circulation increases microchimerism in the offspring. 1B. Determine what bone marrow populations contribute to microchimerism.
Specific Aim 2 : Assess the effect of agents that enhance maternal-fetal microchimerism levels on the phenotype of mucopolysaccharidosis VII mice 2A. Compare the effects of combining stem cell mobilizing agents and agents that increase vascular permeability on maternal microchimerism levels in progeny. 2B. Evaluate the best microchimerism inducing regimen for effect on enzyme level and phenotype of the mucopolysaccharidosis VII progeny. 2C. Compare the best microchimerism inducing regimen to in utero stem cell transplant for effect on phenotype and evaluate the effect on immune tolerance. Techniques used in this project include histochemistry, multicolor flow cytometry, immunohistochemistry, stem cell biology, intra-uterine injections, and immune tolerance studies. Washington University in St. Louis provides an exceptional environment for the training of physician-scientists and will foster the mentored development of the PI towards his goals in academic medicine.
This proposal will train an independent physician-scientist for a career of study about the treatment of inherited diseases and the study of microchimerism. Inherited diseases currently are predominantly untreatable and methods to alleviate the burden of these diseases on the patients and society will be immensely useful. Enhanced knowledge of microchimerism will increase understanding of immune tolerance and the nature of the placental interface and may have far reaching consequences for health and disease.
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