MARROW REGULATION IN CYCLIC HEMATOPOIESIS

描述：（研究者摘要）周期性造血（CH，也称为 周期性中性粒细胞减少症）是一种罕见的血液病，其特征在于 由骨髓产生的血细胞的振荡。CH发生 偶发性和家族性常染色体显性遗传病。以21天 间歇期患者经常出现严重的中性粒细胞减少、口咽部发热 炎症和有时严重的危及生命的感染。疾病 对重组G-CSF和类似物治疗的反应非常有利 常染色体隐性遗传病发生在灰色牧羊犬中， 以14天为周期振荡。该小组以前曾描述过 这种疾病的临床和生理特征及其对 治疗。在他们最近的工作中，他们发现细胞缺陷和 在外周细胞的振荡可能是由于加速细胞凋亡， 骨髓前体细胞他们还发现了常染色体 显性周期性造血映射到19号染色体， 归因于中性粒细胞弹性蛋白酶的突变。在本提案中，我们假设 中性粒细胞弹性蛋白酶的突变，这是早期表达的， CD 34+细胞向髓系分化，导致获得 这种蛋白质的功能或异常功能反过来导致 早期造血细胞凋亡。我们现在建议描述 突变的中性粒细胞弹性蛋白酶及其亚细胞定位，以检查 突变体弹性蛋白酶的酶活性，以研究如何表达 这种蛋白质导致受损的细胞存活，并确定基因和 蛋白质介导其对骨髓祖细胞的调节作用， 这种疾病。这项工作可能会导致这种特定疾病的新疗法， 为中性粒细胞特异性蛋白酶的作用提供了新的见解， 它们的抑制剂在调节中性粒细胞产生和疾病中的作用 导致中性粒细胞减少症。

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.