| Co-Investigator(Kenkyū-buntansha) |
SHIMODA Kazuya Kyushu Univ., Fac. of Med., Res. Assoc., 医学部, 助手 (90311844)
NAKASHIMA Hitoshi Kyushu Univ., Fac. of Med., Res. Assoc., 医学部, 助手 (70188960)
横山 俊宏 九州大学, 医学部, 医員
浅野 嘉延 九州大学, 医学部, 助手 (60271110)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1998: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
G-CSF is known to play an important role in the proliferation, differentiation and functional activation of neutrophilic lineage cells. We tried analysis of G-CSF signal transduction pathway including the cloning of new molecules using the hematopoietic cells form neutrophil disorders.
First, we found the abnormal structure at the juxtamembrane intracellular part of G-CFS receptor, which is important for proliferation signal transduction, in one case with severe congenital neutropenia. This mutated cDNA-transfected cells can not proliferate well in response to G-CSF. On the other hand, we also found another case carrying a mutation at the C-terminal cytoplasmic region, which is important for differentiation signal transduction. Therefore, we can now examine the cells possessing the two types of mutated G-CSF receptor, which can not transduce the proliferation signal or differentiation signal, respectively. Using this method, we may find new molecules to relate the specific function of G
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-CSF.
In addition, we found a new type of soluble G-CSF receptor, which misses the transmembrane part completely. When we tried to compare the function of the new type and common type of soluble G-CSF receptor, there was no difference between the inhibitory effect on the activity of G-CSF. However, the chimeric protein consisting of the extracellular part of the G-CSF receptor and the Fc region of IgG, which is considered to be a good model for new type of soluble G-CSF receptor, could completely inhibit the function of G-CSF.
On the other hand, G-CSF could stimulate the proliferation of AML cells vigorously without functional maturation. Therefore, we analysed the structure of the G-CSF receptor and Jak kinases in many cases with myelogenous leukemia. We found a polymorphism, but no significant pathogenic mutations in any patients. However, we found the unbalanced gene expression of Stat 3 isoform in AML cells. These analysis may be a help to clarify not only the pathogenesis of hematopoietic disorders but also the regulating system of normal hematopoiesis. Less
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