Circulating Endothelial Progenitor Cell Subsets

循环内皮祖细胞亚群

基本信息

批准号：
8261209
负责人：
Laura S Haneline
金额：
$ 13.22万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-26 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8261209
关键词：
Adult Antineoplastic Agents Biological Markers Blood Blood Volume Bone Marrow Chemotherapy-Oncologic Procedure Child Childhood Childhood Solid Neoplasm Clinical Clinical Research Complex Data Development Disease Disease-Free Survival Drug toxicity Effectiveness Endothelial Cells Endothelium Flow Cytometry Functional disorder Future Genes Genetic Genetic Heterogeneity Genotype Growth Factor Hematopoietic Stem Cell Transplantation Hematopoietic stem cells High Dose Chemotherapy In complete remission Indiana Individual Label Malignant - descriptor Malignant Neoplasms Measurement Measures Modeling Modification Morbidity - disease rate Neoplasm Metastasis No Evidence of Disease Operative Surgical Procedures Outcome Pathologic Neovascularization Pathway interactions Patients Pharmaceutical Preparations Radiation therapy Refractory Disease Regulation Research Risk Solid Neoplasm Stem cells Syndrome Testing Time Toxic effect Universities Vascular Diseases Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Vascular remodeling angiogenesis base cell injury chemotherapy density high risk improved indexing mortality novel outcome forecast pediatric pharmacology progenitor repaired response tool tumor

项目摘要

Prognosis remains grim for pediatric patients with high-risk, malignant solid tumors. Children with malignant tumors and children undergoing hematopoietic stem cell transplantation (HSCT) have significant morbidity and mortality due to chemotherapy-induced toxicities. Novel biomarkers based on a distinct biologic profile and on response to therapy are needed to develop individualized therapies and response assessments. Angiogenesis markers have emerged as promising candidates in adult trials. However, pediatric studies are scarce. Our long-term objectives are to identify novel angiogenesis biomarkers in children to promote individualized chemotherapy and to facilitate development of novel therapies. Angiogenesis is coordinated via complex genetic and cellular mechanisms. Vascular endothelial growth factor A (VEGFA), a major growth factor regulating angiogenesis, is encoded by a highly polymorphic gene. Multiple studies demonstrate a correlation between VEGFA genotype and diseases with altered angiogenesis. A major cellular component regulating angiogenesis is circulating endothelial progenitor cells (EPCs). EPCs facilitate endothelial repair and vascular remodeling. Reduced EPCs correlate with clinical indices of endothelial dysfunction and increased risk of vascular disease. Though labeled EPCs, these are hematopoietic progenitors that originate from the bone marrow, not endothelium. Thus, myelotoxic therapies will impact EPCs with subsequent implications for normal and pathologic angiogenesis. Recent advances in flow cytometry allow for enumeration of angiogenic (circulating progenitor cells, CPCs) and non-angiogenic (non-CPCs) progenitors, using blood volumes amenable for implementation in pediatric studies. Our overall hypothesis is that interindividual variability in circulating EPC subsets after chemotherapy will serve as a biomarker for efficacy of malignant solid tumor therapy as well as to predict toxicity after HSCT. In this proposal, we will examine inter-individual variability in chemotherapy response and angiogenesis markers in children. We propose to assess novel angiogenesis markers that include EPC subsets, VEGF genetic heterogeneity, and microvessel density.

对于患有高危，恶性实体瘤的小儿患者，预后仍然很严峻。由于化学疗法诱导的毒性，患有造血干细胞移植（HSCT）的患有造血干细胞移植（HSCT）的儿童具有显着的发病率和死亡率。需要基于独特的生物学特征和对治疗反应的新型生物标志物，以开发个性化的疗法和反应评估。在成人试验中，血管生成标志物已成为有前途的候选人。但是，小儿研究很少。我们的长期目标是确定儿童中新型的血管生成生物标志物，以促进个性化的化学疗法并促进新疗法的发展。血管生成通过复杂的遗传和细胞机制协调。血管内皮生长因子A（VEGFA）是调节血管生成的主要生长因子，由高度多态基因编码。多项研究表明，VEGFA基因型与疾病与血管生成改变之间的相关性。调节血管生成的主要细胞成分是循环内皮祖细胞（EPC）。 EPC促进内皮修复和血管重塑。降低的EPC与内皮功能障碍的临床指数相关增加血管疾病的风险。尽管标有EPC，但这些是造血祖细胞，源自骨髓，而不是内皮。因此，骨髓毒性疗法将影响EPC，随后对正常和病理血管生成的影响。流式细胞仪的最新进展允许使用可在儿科研究中实施的血量来列举血管生成（循环祖细胞，CPC）和非血管生成（非CPC）祖细胞。我们的总体假设是，化学疗法后循环EPC子集的个体差异将成为生物标志物的疗效恶性实体疗法以及预测HSCT后的毒性。在此提案中，我们将检查儿童化学疗法反应和血管生成标志物的个体间变异性。我们建议评估包括EPC子集，VEGF遗传异质性和微舍固密度的新型血管生成标记。