| Budget Amount *help |
¥19,110,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥4,410,000)
Fiscal Year 2010: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2009: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2008: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
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| Research Abstract |
We established xeno-transplantaion model using immune-deficient mice to analyze normal and pathological human hematopoiesis. First we demonstrated that replication stress induces intracellular elevation of reactive oxygen species (ROS) that results in accumulated and persistent DNA damage in human HSCs both in vitro and in vivo. The oxidative DNA damage causes premature senescence among HSCs, leading to loss of stem cell function. Importantly, treatment with an antioxidant can antagonize oxidative DNA damage and consequent HSC dysfunction. Our results reveal that ROS play a causative role for DNA damage, and mechanisms of ROS regulation have a major influence on human HSC aging. Then, to establish suitable in vivo MDS model, we intramedurally transplanted CD34^+ cells from the patients with MDS, acute myelogenous leukemia (AML) derived from MDS (MDS-AML), and AML with trilineage dysplasia into nonobese diabetic/Severe combined immunodeficient/IL-2Rγ^<null> (NOG) mice with co-injection of human mesenchymal stem cells. They were engrafted in bone marrow (BM) of NOG mice, although their efficiency was less than the normal CD34^+ BM cells. Histologically, CD34^+ cells derived from MDS patients were aligned along endosteus of BM, whereas the differentiated cells were located in the central medullary regions. The distribution was abrogated using CD34^+ BM cells from MDS-AML. These findings suggest that this in vivo MDS model is useful for elucidating the pathogenesis of MDS
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