Monocyte derived CXCL7 in the marrow microenvironment

描述(由申请人提供)： 这项建议旨在为首席研究员Manoj Pillai提供将基础科学研究与临床研究相结合的培训经验。基础研究侧重于单核细胞衍生的趋化因子在造血调控中的作用，使用模拟骨髓微环境(ME)的体外系统。临床相关性来自于对正常单核细胞和骨髓增生异常综合征(MDS)患者单核细胞的对比分析，单核细胞功能异常可能与发病有关。培训计划包括科学调查和在贝弗利·托罗克-斯托布博士和雷纳·斯托布博士的指导下进行教学研究。候选人还将受益于约阿希姆·代格博士和拉里·罗施奈德博士的指导，他们将成为他的顾问委员会的成员。 造血的调控是复杂的，涉及几种不同的细胞类型，在ME的背景下协同工作。初步数据表明，单核细胞是ME的组成部分，它会分泌一种趋化因子CXCL7，以响应间质信号。CXCL7多肽之前被报道只来自巨核细胞系的细胞，据报道可以促进成纤维细胞的生长和抑制血小板的生成。建议的研究将检验这样的假设，即基质刺激的单核细胞衍生的CXCL7多肽也影响ME的功能。此外，鉴于初步数据显示MDS患者单核细胞中CXCL7基因异常表达，有待检验的第二个假设是，单核细胞中CXCL7异常表达模式可能与这些患者的发病机制有关。 为了验证这些假说，我们提出了三个具体的目标：(1)使用适当的生物测定方法，利用不同形式的重组蛋白产生的多肽来表征CXCL7多肽对ME的影响。(2)MDS来源的单核细胞表达CXCL7的异常模式将被识别，并与临床数据相关联，以建立异常表达与发病机制之间的联系。(3)在正常单核细胞中，CXCL7基因表达上调的间质信号和后续分子事件将被识别。这将最终描述导致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ME内正常和MDS单核细胞相互作用的后果，这反过来应该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