MOREHOUSE CCRE PP1- ENDOTHELIAL PROGENITOR CELLS IN SICKLE CELL DISEASE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 为了更好地了解镰状细胞病的血管病变，我们有兴趣测量镰状细胞病患者的EPC数量和功能，并确定慢性红细胞输注治疗是否可以纠正数量或功能异常。 我们假设，循环内皮祖细胞的数量增加，镰状细胞病相对于正常对照组，由于造血生长因子水平的增加和持续的血管损伤，由于血管闭塞事件。虽然未输血的镰状细胞受试者的EPC数量可能会增加，但我们推测它们会损害血管形成并增加氧化剂的产生。 输血治疗，通过降低促红细胞生成素的产生，将降低镰状细胞患者循环EPCs的数量，并可能恢复EPCs的正常功能。 镰状细胞血管病变中的EPC生物学从未被研究过。 在这个试点项目中，我们建议调查镰状细胞病患者是否有异常的EPC数量或功能。 阐明这些关系将提高我们对这种疾病的一些致残性并发症的病因学的理解，并提高我们开发针对性治疗干预措施以治疗和预防镰状细胞血管并发症的能力。 假设 1. 与正常对照相比，镰状细胞病患者的循环EPCs和生长细胞数量增加，并伴有促红细胞生成素水平升高。 2. 来自Hb SS受试者的EPC与来自正常对照的EPC相比具有减少的血管管形成。 3. 与正常对照相比，来自具有Hb SS的受试者的EPC将具有促氧化表型。 4. 与未输血的镰状细胞病受试者相比，接受红细胞输注治疗的镰状细胞病受试者的促红细胞生成素水平降低，循环EPC和生长细胞数量减少，血管管形成更好，氧化剂表达减少。 具体目标 1. 定量从三组受试者的外周血中分离的循环EPC的数量：血红蛋白AA（正常）、无慢性输血的血红蛋白SS和慢性输血的血红蛋白SS。 2. 定量三组中来源于EPCs的生长细胞的数量及其衰老速率。 3. 测量三组受试者的EPCs的血管管形成。 4. 检测三组EPCs细胞内活性氧、超氧化物水平和黄嘌呤氧化酶活性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To better understand the vasculopathy of sickle cell disease, we are interested in measuring EPC number and function in people with sickle cell disease and determining whether chronic erythrocyte transfusion therapy corrects abnormalities in number or function. We hypothesize that the number of circulating EPCs are increased in individuals with sickle cell disease relative to normal controls due to increased levels of hematopoietic growth factors and ongoing vessel injury due to vaso-occlusive events. While numbers of EPCs in untransfused sickle cell subjects are likely to be increased, we postulate that they will have impaired vascular tube formation and increased oxidant production. Transfusion therapy, by lowering erythropoietin production, will lower the numbers of circulating EPCs in sickle cell subjects and may restore normal function to EPCs. EPC biology in sickle cell vasculopathy has never been studied. In this pilot project, we propose to investigate whether people with sickle cell disease have abnormal EPC number or function. Elucidation of these relationships will improve our understanding of the etiology of some of the disabling complications of this disease and enhance our ability to develop targeted therapeutic interventions for treatment and prevention of sickle cell vascular complications. HYPOTHESES 1. Individuals with sickle cell disease will have increased numbers of circulating EPCs and outgrowth cells than normal controls, in association with elevated levels of erythropoietin. 2. EPCs from subjects with Hb SS will have reduced vascular tube formation than those from normal controls. 3. EPCs from subjects with Hb SS will have a pro-oxidant phenotype compared to normal controls. 4. Subjects with sickle cell disease receiving red cell transfusion therapy will have reduced erythropoietin levels, lower numbers of circulating EPCs and outgrowth cells, better vascular tube formation and reduced oxidant expression than untransfused sickle cell subjects. SPECIFIC AIMS 1. Quantitate the number of circulating EPCs isolated from the peripheral blood of three groups of subjects: Hemoglobin AA (normal), hemoglobin SS without chronic transfusions, and hemoglobin SS on chronic transfusions. 2. Quantitate the number of outgrowth cells derived from EPCs and their rates of senescence in the three groups. 3. Measure vascular tube formation of EPCs from subjects in the three groups. 4. Measure intracellular reactive oxygen species, superoxide levels, and xanthine oxidase activity in the EPCs from the three groups.