Effects of nicotine on hematopoietic stem cell migration
Initial Award Abstract
Hematopoiesis, generation of mature blood cells, is vital for life: the white cells fight infections, the red cells carry oxygen throughout the body, and the platelets promote healing and prevent bleeding. The hematopoietic stem cell is a progenitor cell that generates all varieties of mature blood cells throughout life. Hematopoietic stem cells are found in the bone marrow, where they continue to generate mature blood cells throughout our lives. Thus, any changes in the ability of stem cells to function normally could be deleterious to the body. Current treatments, such as irradiation or cytotoxic chemotherapy, result in serious alterations in the bone marrow, resulting in an imbalance of the hematopoietic homeostasis and a dramatically decreased number of hematopoietic stem cells and mature cells in the bone marrow and peripheral blood. These patients are subjected to the transplantation of hematopoietic stem cells in order to reconstitute hematopoietic activity in the bone marrow. These transplanted hematopoietic stem cells find their way to the bone marrow because of their sensitivity to stroma-derived factor-1 (SDF-1) a chemoattractant produced by bone marrow stroma.
We found that nicotine, a major constituent of tobacco and cigarette smoke, inhibits SDF-1 mediated migration of hematopoietic stem cells. Based on our preliminary observations, we propose to investigate how nicotine affects stem cell migration. We plan to examine which cells have a receptor for nicotine on their cell surface and, therefore, can respond to its action. We further propose to investigate which molecules mediate the deleterious effects of nicotine on hematopoietic stem cell migration. Finally, we attempt to discover whether the harmful effects on nicotine can be prevented by specific antagonists, molecules that compete with nicotine for the receptor.
The studies proposed in the current application are planned with a view to obtain a better understanding of the cellular and molecular mechanisms of the pathophysiological effects of nicotine. We are confident that these planned studies will provide an explanation of how nicotine affects trafficking of hematopoietic stem cells in the bone marrow. Studying the effect of nicotine on the bone marrow may open a new area of research which could ultimately establish a basis for novel therapeutic approaches to the treatment of tobacco-related diseases. |