ENDOMETRIOTIC HAPTOGLOBIN ALTERS MACROPHAGE FUNCTION

描述（由申请人提供）：子宫内膜异位症在美国和加拿大影响550万育龄妇女和女孩，在世界范围内影响数百万，导致盆腔疼痛和不孕症。诊断和治疗需要昂贵的侵入性手术来识别和切除异位子宫内膜组织。子宫内膜异位症是美国子宫切除术的三大原因之一；每年有超过50万例子宫切除术，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明确。本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症分泌蛋白，开发新的医疗管理方法。这项研究源于发现子宫内膜异位症病变实际上合成和分泌触珠蛋白（Hp）。有趣的是，与肝Hp相比，子宫内膜异位性接触珠蛋白（eHp）的糖基化是不同的。初步数据支持eHp在异常免疫现象中的病理相关作用，这些异常免疫现象支持子宫内膜异位症妇女的疾病过程。待验证的假设是，子宫内膜异位症女性的子宫内膜异位症组织通过表达eHp，避免了吞噬细胞的消灭，同时刺激了腹膜巨噬细胞炎性细胞因子的分泌。反过来，巨噬细胞因子增加子宫内膜异位症组织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建立。

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.