MARROW REGULATION IN CYCLIC HEMATOPOIESIS

描述：(研究人员摘要)周期性造血(CH，又称 循环中性粒细胞减少症)是一种罕见的血液系统疾病，其特征是 骨髓产生血细胞的振荡过程。CH发生 散发性和家族性常染色体显性遗传病。在第21天 间歇期患者常有严重的中性粒细胞减少、口腔咽部发热 炎症，有时还会有严重的危及生命的感染。这种病 对重组G-CSF和类似物的治疗反应非常好 常染色体隐性遗传病发生在血细胞数量较少的灰色牧羊犬 以14天为周期振荡。该组织此前曾将 该病的临床和生理特点及其对疾病的反应 治疗。在他们最新的研究中，他们发现细胞缺陷和 外周细胞的振荡可能是由于加速了细胞的凋亡 骨髓前体细胞。他们还发现了常染色体的遗传位点。 显性周期造血映射到19号染色体，这种疾病是 可归因于中性粒细胞弹性蛋白酶的突变。在这个提案中，我们假设 中性粒细胞弹性蛋白酶的突变，它在早期表达 将CD34+细胞分化为髓系，导致获得 这种蛋白质的功能或异常功能进而导致 早期造血细胞凋亡性死亡。我们现在建议将其描述为 突变的中性粒细胞弹性蛋白酶及其亚细胞定位 突变的弹性蛋白酶的酶活性，以考察如何表达 导致细胞存活受损，并确定基因和 介导其对髓系祖细胞的调节作用的蛋白质 这种病。这项工作可能会为这种特殊疾病带来新的治疗方法 为中性粒细胞特异性蛋白水解酶的作用提供新的见解 它们在中性粒细胞产生和疾病中的调节作用 导致中性粒细胞减少。

DESCRIPTION: (Investigator's abstract) Cyclic hematopoiesis (CH, also called cyclic neutropenia) is a rare hematological disorder characterized by oscillatory production of blood cells by the bone marrow. CH occurs sporadically and in families as an autosomal dominant disorder. At 21 day intervals patients regularly have severe neutropenia, fever oral pharyngeal inflammation and on occasion severe life threatening infections. The disease responds very favorably to treatment with recombinant G-CSF and analogous autosomal recessive disease occurs in grey collie dogs whose blood cells oscillate with 14-day periodicity. This group has previously characterized the clinical and physiological features of this disease and its response to treatments. In their most recent work, they found that the cellular defect and oscillations in peripheral cells are probably due to accelerated apoptosis of marrow precursors. They have also found the genetic locus for autosomal dominant cyclic hematopoiesis maps to chromosome 19 and the disease is attributable a mutation in neutrophil elastase. In this proposal we hypothesize that the mutation of neutrophil elastase, which is expressed early in the differentiation of CD34+ cells to the myeloid lineage, leads to a gain of function or an aberrant function of this protein which in turn leads to the apoptotic death of early hematopoietic cells. We propose now to characterize the mutant neutrophil elastase and its subcellular localizations, to examine the enzymatic activities of the mutant elastase, to investigate how expression of this protein leads to impaired cell survival and to determine the genes and proteins which mediate its regulatory effects on myeloid progenitor cells in this disease. This work may lead to new therapies for this specific disease and provide new insights into the role of the neutrophil specific proteases and their inhibitors in the regulation of neutrophil production and in disease causing neutropenia.