SIGNAL TRANSDUCTION THROUGH TH ERYTHROPOIETIN RECEPTOR

描述(申请人的描述)：红细胞生成是一种高度受监管的 多能造血祖细胞的发育过程 细胞致力于分化为红系前体细胞 对促红细胞生成素和其他生长因子的反应。.的存在 促红细胞生成素和c-Kit受体是这一过程发生的关键。 通常是这样的。然而，目前尚不清楚这些受体是否具有特异性 “指示”祖细胞沿着特定的谱系或 如果它们只是让细胞存活足够长的时间，这样它们就可以 沿着随机程序进行区分。 这个应用程序试图在生理环境中解决这个问题 整个小鼠，利用胚胎干细胞技术以及使用 逆转录病毒感染初级造血祖细胞。的作用 通过观察不同基因的表达对细胞凋亡的影响 C-IAPs、c-IAPs等基因 BaF3和HCD-57细胞系向祖细胞分化的研究 从胎儿肝脏中提取。串联质谱仪在蛋白质研究中的应用 将利用测序方法(MALDI-MS/MS)来识别信号 当EpoR被EPO激活时，S和S与EpoR相互作用的分子。自.以来 几种红细胞疾病中的分子/发育缺陷 真性红细胞增多症和红白血病尚不清楚，很可能是 这些研究将导致识别可能有缺陷的分子。 或提供对发育异常的洞察力 这会导致骨髓增生。最后，信号的性质 真性红细胞增多症的缺陷将被研究。它将被确定是否 造血细胞对EPO的高反应性 影响负性功能的表达模式或突变 SH-PTP1和CIS(细胞因子诱导的SH2)等信号调节剂 域)。

DESCRIPTION (Applicant's Description): Erythropoiesis is a highly regulated developmental process during which pluripotent hematopoietic progenitor cells become committed to differentiate into erythroid precursors in response to erythropoietin and other growth factors. The presence of erythropoietin and c-Kit receptors is critical for this process to occur normally. It is not known, however, whether these receptors specifically "instruct" progenitor cells to differentiate along a particular lineage or if they merely allow the cells to survive long enough so they can then differentiate along a stochastic program. This application seeks to address this issue in the physiological setting of the whole mouse, utilizing embryonic stem cell technology as well as the use of retroviruses to infect primary hematopoietic progenitors. The role of apoptosis will be examined by looking at the effect of expression of various a n ti-apoptotic genes such as Bcl-2, Bcl-x, CrmA, and c-IAPs on the differentiation of BaF3 and HCD-57 cell lines in addition to progenitors derived from fetal livers. Tandem mass spectrometry based protein sequencing approaches (MALDI-MS/MS) will be utilized to identify signaling molecules that a s s ociate with the EpoR when it is activated by Epo. Since the m o lecular/developmental defect in several red cell disorders such as polycythemia vera and erythroleukemias is not yet known, it is likely that these studies will lead to identification of molecules that may be defective in these diseases or provide insights into the developmental abnormality that leads to bone marrow hyperplasia. Finally, the nature of the signaling defect in polycythemia vera will be studied. It will be determined if the hyperresponsiveness of hematopoietic cells to Epo results from altered expression patterns or mutations affecting the function of negative modulators of signaling such as SH-PTP1 and CIS (Cytokine Inducible SH2 domain).