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Gap Junction Intercellular Communication in Bone Marrow Failure

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Final rept. 1 Apr 2011-30 Sep 2012

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The mechanisms responsible for both acquired and inherited bone marrow failure BMF are not yet understood. Although most inherited BMF syndromes can be linked to specific genetic defects, these defects do not fully explain the range of physical characteristics observed in affected individuals. In addition, animal models for observed BMF genetic defects have not been able to fully recreate the associated syndromes. With support from a Fiscal Year 2010 Bone Marrow Failure Research Program Exploration Hypothesis Development Award, Dr. Cancelas is investigating whether BMF syndromes are related to a defect in cell-to-cell communication between mesenchymal stem cells and progenitors MSCP and hematopoietic stem cells HSC. Blood cell formation in the bone marrow hematopoiesis is dependent on the close association of HSC and the surrounding microenvironment, of which MSCP are a major component.Natural causes such as aging, or external insults, such as radiation, toxin exposure, or chemotherapy, are known to cause DNA damage and affect HSC activity, which may in part be due to hematopoietic stress from increasing cellular levels of reactive oxygen species ROS. Fanconi anemia and Schwachman-Diamond syndrome are two BMF syndromes with defects in DNA repair enzyme systems, making individuals with these syndromes highly sensitive to DNA-damaging events. However, researchers suspect that modifier genes or traits are responsible for the differences in the severity of these diseases and their relation to skeletal malformations in BMF syndromes. Using a model of DNA damage induced by chemotherapy-induced ROS production, Dr. Cancelas tested the ability of HSC to resume blood formation after hematopoietic stress. His results indicated that hematopoietic recovery is delayed when HSC are deficient in connexin-43 Cx43, a gap junction protein involved in cell-to-cell communication and highly expressed in HSC and MSCP.

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  • Medicine and Medical Research
  • Stress Physiology

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