Monocyte derived CXCL7 in the marrow microenvironment

本提案旨在为主要研究者Manoj Pillai提供培训经验， 将基础科学研究与临床研究相结合。基础研究集中在单核细胞衍生的作用 趋化因子在造血调节中的作用，使用模拟骨髓的体外系统 微环境（ME）临床相关性来自于正常单核细胞与 来自骨髓增生异常综合征（MDS）患者的那些，其中异常的单核细胞功能可能是 与发病机制有关。培训计划包括科学调查和教学研究， 贝弗莉·托罗克·斯托布博士和雷纳·斯托布博士的指导此外，申请人亦可从 Joachim Deeg博士和Larry Rohrschneider博士的指导，他们将成为他的咨询委员会的一员。 造血的调节是复杂的，涉及几种不同的细胞类型，在造血系统中协同工作。 初步数据表明，单核细胞，这是一个完整的组成部分，ME 分泌趋化因子CXCL7以响应基质信号。CXCL7肽，以前报道是 仅来源于巨核细胞谱系的细胞，据报道可增加成纤维细胞生长并抑制 血小板生成。拟议的研究将检验基质刺激的单核细胞衍生的 CXCL7肽也影响ME的功能。此外，鉴于初步数据表明， MDS患者单核细胞中CXCL7基因表达，待检验的第二个假设是， 单核细胞中CXCL 7表达的异常模式可能有助于这些患者的发病机制。 本研究提出了三个具体的目的来检验这些假设：（1）利用适当的生物测定方法， ME上的CXCL 7肽将使用产生的不同形式的肽表征， 重组蛋白(2)MDS来源的单核细胞表达CXCL7的异常模式将被视为 确定并与临床数据相关联，以建立异常表达与 发病机制(3)基质信号和随后的分子事件负责上调 将鉴定正常单核细胞中的CXCL7基因表达。这将有助于最终划定 导致MDS单核细胞异常表达的机制。这些研究的数据应该 有助于准确理解正常和MDS单核细胞相互作用的后果， ME，这反过来又会导致新干预措施的发展。

This proposal is designed to provide the Principal Investigator, Manoj Pillai, with a training experience that combines basic science research with clinical research. Basic studies focus on the role of monocyte-derived chemokines in the regulation of hematopoiesis, using in-vitro systems that model the marrow microenvironment (ME). Clinical correlates come from a comparative analysis of normal monocytes with those from patients with myelodysplastic syndrome (MDS), where abnormal monocyte function may be associated with pathogenesis. The training program involves scientific investigation and didactic study under the mentorship of Dr. Beverly Torok-Storb and Dr. Rainer Storb. The applicant will also benefit from the guidance of Dr. Joachim Deeg and Dr. Larry Rohrschneider, who will be part of his advisory committee. The regulation of hematopoiesis is complex, involving several different cell types, working in concert in the context of the ME. Preliminary data indicate that monocytes, which are an integral component of the ME secrete a chemokine, CXCL7, in response to stromal signals. CXCL7 peptides, previously reported to be derived only from cells of the megakaryocyte lineage, are reported to augment fibroblast growth and inhibit platelet production. The proposed studies will test the hypothesis that stromal-stimulated monocyte-derived CXCL7 peptides also affect the function of the ME. In addition, given that preliminary data suggest abnormal CXCL7 gene expression in monocytes from MDS patients, a second hypothesis to be tested is that abnormal patterns of CXCL7 expression in monocytes may contribute to pathogenesis in these patients. Three Specific Aims are proposed to test these hypotheses: (1) Using appropriate bioassays, the effect of CXCL7 peptides on the ME will be characterized using different forms of the peptide generated as recombinant proteins. (2) Abnormal patterns of CXCL7 expression by MDS-derived monocytes will be identified and correlated with clinical data to establish an association between abnormal expression and pathogenesis. (3) The stromal signals and subsequent molecular events responsible for the up regulation of CXCL7 gene expression in normal monocytes will be identified. This will allow for eventual delineation of mechanisms responsible for aberrant expression in MDS monocytes. Data from these studies should contribute to a precise understanding of the consequences of normal and MDS monocyte interactions within the ME, which in turn should lead to the development of novel interventions.