CMG2 as a target for safe and effective treatment of endometriosis-associate pain

CMG2 作为安全有效治疗子宫内膜异位症相关疼痛的靶点

• 批准号: 10583339
• 负责人: MICHAEL SEAN ROGERS
• 金额: $ 175.85万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583339
• 关键词: ANTXR2 gene; Affect; Analgesics; Biological; Biological Assay; Biology; Blood capillaries; Catalytic Domain; Cells; Cellular biology; Chemotaxis; Chronic; Chronic Disease; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Disease; Disease model; Drug Targeting; ECM receptor; Endometrial; Endometrium; Endothelial Cells; Epithelial Cells; Estrogens; Female; Female of child bearing age; Fetal Development; Fibrosis; Financial compensation; Functional disorder; Gene Expression Profile; Generations; Genes; Growth; Hormonal; Human; Incidence; Individual; Infertility; Inflammatory; Integrins; Intervention; Knock-out; Knockout Mice; Knowledge; Lead; Lesion; Litter Size; Measures; Mediating; Mediator of activation protein; Medical; Modeling; Molecular; Morphogenesis; Mus; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Opiate Addiction; Opioid; Oral; Overdose; Pain; Pain management; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Physiological; Population; Production; Program Development; Proteins; Proteomics; Publishing; Reagent; Risk; Role; Safety; Signal Transduction; Specificity; Stromal Cells; Therapeutic; Tissues; Uterus; Woman; Work; angiogenesis; antagonist; base; cell type; chronic pain; chronic pelvic pain; clinical development; drug action; drug development; drug discovery; effective therapy; endometriosis; eutopic endometrium; high throughput screening; hormone therapy; implantation; improved; in vitro Assay; in vivo; inhibitor; insight; knockout animal; mouse model; non-opioid analgesic; novel; novel strategies; novel therapeutics; ocular angiogenesis; opioid overdose; opioid use; overexpression; pain relief; pharmacodynamic biomarker; response; side effect; small molecule; targeted treatment; therapeutic development; therapeutic target; transcriptome sequencing; treatment effect

Endometriosis-associated pain is an important driver of opioid use in women. Endometriosis is and estrogen sensitive, angiogenesis dependent disease that affects ~10% of women of childbearing age and is found in half of women with chronic pelvic pain. Endometriosis increases the likelihood of chronic opioid use, opioid dependence/abuse, and opioid overdose. Endometriosis is currently treated with NSAIDS, hormonal therapy targeting estrogen production, and surgery, but these options are not durably effective for ~30% of patients. Thus, new targets are needed. CMG2 is an integrin-like extracellular matrix receptor that we have shown regulates angiogenesis. It is also overexpressed in endometriosis tissue vs. normal endometrium. In mouse models, published work and our preliminary data show that treatment with CMG2 antagonists that we discovered (PGG, PGM) decreases lesion incidence, growth, and endometriosis-associated pain. These observations suggest that CMG2 may be a useful target for the treatment of endometriosis-associated pain. However, key gaps in our understanding of CMG2 biology would slow any development program with CMG2 as a target. The first key gap is that the cell type whose targeting resulted in decreased pain upon CMG2 antagonist treatment is unclear. Second, the molecular mechanism underlying CMG2 signaling in endometriosis is not known. Finally, both the maximum efficacy and, importantly, safety of CMG2 targeting is not known. We propose to fill these gaps by using cell-type-specific CMG2 knockout mice to identify cell types where CMG2 expression supports endometriosis lesion growth and pain. Because CMG2 lacks any catalytic domains, we hypothesize that CMG2 signals via differential protein interaction. Then, expression of CMG2 in appropriate cells in human lesions will be confirmed. Next, we will use proximity proteomics to identify downstream molecules that differentially interact with CMG2 ±inhibitor. Candidate mediators of CMG2 signaling will then be confirmed using CRISPR knockout and cell-based assays of CMG2 function. Finally, we will evaluate safety and efficacy of CMG2 targeting in a mouse model using a well-characterized, high- specificity CMG2 inhibitor. Throughout ex vivo and in vivo assays, RNAseq and scRNAseq will be used to identify transcriptional signatures of CMG2 blockade, both to validate in vitro assays and to generate potential pharmacodynamic markers of CMG2 inhibitors. Completion of the proposed work will validate CMG2 as a target for the treatment of endometriosis- associated pain. It will also provide key insights into endometriosis pathophysiology that will enable the generation of novel therapeutics and may identify additional targets for treatment of the disease. Development of such drugs will improve the lives of many women and decrease the use of opiods to treat this disease, thereby improving many lives.

子宫内膜异位症相关疼痛是女性使用阿片类药物的一个重要驱动因素。子宫内膜异位症是 雌激素敏感型血管生成依赖型疾病，影响约10%的育龄妇女， 在一半患有慢性盆腔疼痛的女性身上发现。子宫内膜异位症增加了长期使用阿片类药物的可能性， 阿片依赖/滥用和阿片类药物过量。子宫内膜异位症目前使用非类固醇、激素治疗 针对雌激素产生和手术的治疗，但这些选择在~30%的时间内不是持久有效的 病人。因此，需要新的目标。 CMG2是一种整合素样细胞外基质受体，我们已经证明它可以调节血管生成。它是 在子宫内膜异位症组织和正常子宫内膜中也有过表达。在小鼠模型中，已发表的工作和 我们的初步数据显示，我们发现的CMG2拮抗剂(PGG，PGM)的治疗减少 病变发生率、生长和子宫内膜异位症相关疼痛。这些观察结果表明，CMG2可能是 是治疗子宫内膜异位症相关疼痛的有用靶点。然而，我们对 CMG2生物学将减缓任何以CMG2为目标的开发计划。第一个关键差距是单元格 靶向导致CMG2拮抗剂治疗后疼痛减轻的类型尚不清楚。第二， 子宫内膜异位症中CMG2信号转导的分子机制尚不清楚。最后，既是最大的 CMG2靶向的有效性和安全性尚不清楚。 我们建议通过使用特定细胞类型的CMG2基因敲除小鼠来确定细胞类型，从而填补这些空白 CMG2的表达支持子宫内膜异位症病变的生长和疼痛。因为CMG2缺乏任何催化作用 我们假设CMG2是通过差异蛋白质相互作用来传递信号的。然后，CMG2在大肠杆菌中的表达 人体损伤中合适的细胞将得到确认。接下来，我们将使用邻近蛋白质组学来识别 与CMG2±抑制物有差异相互作用的下游分子。CMG2的候选调解人 然后将使用CRISPR基因敲除和基于细胞的CMG2功能分析来确认信号转导。最后，我们 将在小鼠模型中评估CMG2靶向的安全性和有效性，使用具有良好特征的、高度集中的 特异性CMG2抑制剂。在整个体外和体内检测中，RNAseq和scRNAseq将用于 确定CMG2阻滞剂的转录特征，以验证体外分析并产生潜力 CMG2抑制剂的药效学标志物。 拟议工作的完成将验证CMG2作为治疗子宫内膜异位症的目标- 伴随的疼痛。它还将提供对子宫内膜异位症病理生理学的关键见解，使 产生新的治疗方法，并可能确定治疗该疾病的其他靶点。发展 这类药物的使用将改善许多女性的生活，减少阿片类药物治疗这种疾病的使用， 从而改善了许多人的生活。