Monocyte derived CXCL7 in the marrow microenvironment

描述（由申请人提供）： 该提案旨在为主要研究者Manoj Pillai提供将基础科学研究与临床研究相结合的培训经验。基础研究集中在单核细胞衍生的趋化因子在造血调控中的作用，使用体外系统模拟骨髓微环境（ME）。临床相关性来自正常单核细胞与骨髓增生异常综合征（MDS）患者的比较分析，其中异常单核细胞功能可能与发病机制相关。培训计划包括在Beverly Torok-Storb博士和Rainer Storb博士的指导下进行科学调查和教学研究。候选人还将受益于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，在一致的上下文中的ME。初步数据表明，单核细胞，这是一个不可分割的组成部分ME分泌趋化因子，CXCL 7，在响应基质信号。CXCL 7肽，以前报道仅来源于巨核细胞谱系的细胞，据报道增加成纤维细胞生长和抑制血小板产生。拟议的研究将测试的假设，即基质刺激单核细胞衍生的CXCL 7肽也影响ME的功能。此外，鉴于初步数据表明异常的CXCL 7基因表达的MDS患者的单核细胞，第二个假设进行测试是，异常模式的CXCL 7表达的单核细胞可能有助于这些患者的发病机制。 提出了三个具体目的来检验这些假设：（1）使用适当的生物测定，使用作为重组蛋白产生的不同形式的肽来表征CXCL 7肽对ME的影响。(2)MDS衍生的单核细胞的CXCL 7表达的异常模式将被鉴定并与临床数据相关联，以建立异常表达与发病机制之间的关联。(3)将鉴定负责正常单核细胞中CXCL 7基因表达上调的基质信号和随后的分子事件。这将允许最终描绘MDS单核细胞中异常表达的机制。这些研究的数据应该有助于精确理解ME内正常和MDS单核细胞相互作用的后果，这反过来又会导致新干预措施的开发

DESCRIPTION (provided by applicant): 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 candidate 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