ENDOMETRIOTIC HAPTOGLOBIN ALTERS MACROPHAGE FUNCTION

子宫内膜异位触珠蛋白改变巨噬细胞功能

基本信息

批准号：
7030945
负责人：
KATHY L TIMMS
金额：
$ 31.86万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2008-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Endometriosis affects 5 1/2 million reproductive age women and girls in the USA and Canada, and millions more worldwide, causing pelvic pain and infertility. Diagnosis and treatment require costly, invasive surgery to identify and ablate ectopic endometrial tissue. Endometriosis is one of the three top reasons for hysterectomy in the USA; over 1/2 million hysterectomies are performed annually at an estimated cost of more than $5 billion. Yet, the pathogenesis of endometriosis remains poorly defined. The long-term objectives of this research are to develop novel methods of medical management by characterizing endometriotic secretory proteins that correlate with the cellular and molecular pathogenic mechanisms of endometriosis. This research evolves from the discovery that endometriotic lesions actually synthesize and secrete haptoglobin (Hp). Intriguingly, endometriotic haptoglobin (eHp) is differentially glycosylated compared to hepatic Hp. Preliminary data support a pathologically relevant role for eHp in the aberrant immunological phenomena that support the disease process in women with endometriosis. The hypothesis to be tested is that by expressing eHp, endometriotic tissues from women with endometriosis avoid phagocytic eradication while stimulating peritoneal macrophage inflammatory cytokine secretion. In turn, the macrophage cytokines increase endometriotic tissue eHp production, creating a local, feed-forward loop between ectopic endometrium and macrophages favoring the establishment of endometriosis. To test this hypothesis, peritoneal macrophages, and endometriotic lesions when present, will be collected from women without and with endometriosis. These immune cells and tissues will be used to investigate three specific aims: 1) Identify the effects of eHp on peritoneal macrophage phagocytosis by analyzing the five steps of macrophage function in vitro including chemotaxis, adherence, ingestion, oxidative metabolism and activation. 2) Characterize a ligand/receptor mechanism whereby eHp causes aberrant macrophage function, by selectively altering eHp glycans and/or blocking peritoneal macrophage integrins. 3) Quantify the effects of macrophage inflammatory cytokines and growth factors on eHp synthesis and secretion. These experiments will provide insight into the pathogenesis of endometriosis by determining if endometriotic tissues, peritoneal macrophages or both are responsible for this pathology, if this mechanism is unique to women with endometriosis and confirm our feedforward hypothesis. As a result, novel non-invasive strategies for early detection and innovative treatment of endometriosis may be developed that markedly reduce the health burden of this malady.

描述（由申请人提供）：子宫内膜异位症影响美国和加拿大的 5.5 万育龄妇女和女孩，以及全世界数以百万计的妇女和女孩，导致骨盆疼痛和不孕。诊断和治疗需要昂贵的侵入性手术来识别和消融异位子宫内膜组织。子宫内膜异位症是美国子宫切除术的三大原因之一；每年进行超过二分之一的子宫切除术，估计费用超过 50 亿美元。然而，子宫内膜异位症的发病机制仍不清楚。这项研究的长期目标是通过表征与子宫内膜异位症的细胞和分子致病机制相关的子宫内膜异位分泌蛋白来开发新的医疗管理方法。这项研究源于子宫内膜异位病变实际上合成和分泌触珠蛋白 (Hp) 的发现。有趣的是，与肝脏 Hp 相比，子宫内膜异位结合珠蛋白 (eHp) 的糖基化存在差异。初步数据支持 eHp 在支持子宫内膜异位症女性疾病过程的异常免疫现象中发挥病理相关作用。待检验的假设是，通过表达 eHp，子宫内膜异位症女性的子宫内膜异位组织避免了吞噬细胞的根除，同时刺激腹膜巨噬细胞炎症细胞因子的分泌。反过来，巨噬细胞细胞因子增加子宫内膜异位组织 eHp 的产生，在异位子宫内膜和巨噬细胞之间形成局部前馈回路，有利于子宫内膜异位症的形成。为了检验这一假设，将从患有和患有子宫内膜异位症的女性身上收集腹膜巨噬细胞和子宫内膜异位病变（如果存在）。这些免疫细胞和组织将用于研究三个具体目标：1）通过分析体外巨噬细胞功能的五个步骤，包括趋化、粘附、摄取、氧化代谢和激活，确定eHp对腹腔巨噬细胞吞噬作用的影响。 2) 表征配体/受体机制，通过选择性改变 eHp 聚糖和/或阻断腹膜巨噬细胞整合素，eHp 导致巨噬细胞功能异常。 3）量化巨噬细胞炎症细胞因子和生长因子对eHp合成和分泌的影响。这些实验将通过确定子宫内膜异位组织、腹膜巨噬细胞或两者是否对子宫内膜异位症的病理学负责，如果这种机制是患有子宫内膜异位症的女性所独有，并证实我们的前馈假设，从而深入了解子宫内膜异位症的发病机制。因此，可以开发出用于子宫内膜异位症早期检测和创新治疗的新型非侵入性策略，从而显着减轻这种疾病的健康负担。