MOLECULAR GENETIC BASIS OF CYCLIC HEMATOPOIESIS

人周期性造血（也称为周期性中性粒细胞减少症，MIM #162800）是一种常染色体显性疾病，其中循环血细胞计数以不变的21天周期振荡，这是由骨髓产生细胞的周期性波动引起的。血细胞计数的循环对于中性粒细胞和单核细胞最为明显，中性粒细胞在血小板减少最低点期间引起机会性感染，单核细胞的循环与中性粒细胞的循环相反。在初步研究中，遗传连锁分析已被用于将周期性造血的基因座定位到染色体19 p13。（在θ = 0时最大2点LOD得分为13.1）和位置克隆策略，在编码嗜中性粒细胞弹性蛋白酶的基因中鉴定了7个不同的单碱基取代，嗜中性粒细胞弹性蛋白酶是嗜中性粒细胞和单核细胞颗粒的胰凝乳蛋白酶丝氨酸蛋白酶，在13个家庭中的13个中，以及在一个散发病例中的新突变。神经弹性蛋白酶是α-1-抗胰蛋白酶抑制蛋白酶的靶点，其无对抗释放参与炎症部位的组织损伤。负责周期性造血的突变集中在涉及底物特异性和与α-1-抗胰蛋白酶相互作用的分子区域。我们假设中性粒细胞弹性蛋白酶及其抑制剂或其他生化异常之间的干扰相互作用可能会中断反馈回路，从而导致造血循环。我们提出了特定的目的，以调查所观察到的突变的分子遗传效应，并计划通过一个转基因小鼠模型，包含各种人类构建体交叉到遗传背景，修改中性粒细胞弹性蛋白酶和α-1-抗胰蛋白酶的相互作用，将生化缺陷的造血循环的生物学观察。广泛的长期目标是了解骨髓的21天生物钟，其周期在这种疾病中很明显。

Human cyclic hematopoiesis (also known as cyclic neutropenia, MIM #162800) is an autosomal dominant disease in which circulating blood cell counts oscillate with an invariant 21 day period resulting from periodic fluctuations in the production of cells by the bone marrow. The cycling of blood counts is most pronounced for neutrophils, causing opportunistic infections to arise during the neutropenic nadir, and monocytes, which cycle in a phase opposite to that of neutrophils. In preliminary studies genetic linkage analysis has been used to map the locus for cyclic hematopoiesis to chromosome 19p13.3 (maximum 2-point LOD score of 13.1 at theta = 0) and with a positional cloning strategy 7 different single base substitutions have been identified in the gene encoding neutrophil elastase, a chymotryptic serine protease of neutrophil and monocyte granules, in 13 of 13 families as well as a new mutation in one sporadic case. Neutrophil elastase is the target for protease inhibition by alpha-1-antitrypsin, and its unopposed release is involved in tissue damage at sites of inflammation. The mutations responsible for cyclic hematopoiesis cluster in regions of the molecule implicated in substrate specificity and interaction with alpha-1- antitrypsin. We hypothesize that a perturbed interaction between neutrophil elastase and its inhibitors or other biochemical abnormality may interrupt a feedback circuit and thereby lead to hematopoietic cycling. We propose Specific Aims to investigate the molecular genetic effects of the observed mutations and plan to link the biochemical deficit to the biological observation of hematopoietic cycling through a transgenic mouse model containing various human constructs crossed into genetic backgrounds which modify neutrophil elastase and alpha-1-antitrypsin interactions. The broad, long-term objective is to understand the 21 day biological clock of the bone marrow, whose cycle is made evident in this disease.