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

基本信息

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
项目类别：
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

项目摘要

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重要驱动因素。雌激素敏感、血管生成依赖性疾病，影响约 10% 的育龄妇女，并且一半患有慢性盆腔疼痛的女性会增加长期使用阿片类药物的可能性，阿片类药物依赖/滥用和阿片类药物过量目前用非甾体抗炎药、激素治疗。针对雌激素产生的治疗和手术，但这些选择对于约 30% 的患者来说并不能持久有效。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。在小鼠模型中，与正常子宫内膜相比，在子宫内膜异位组织中也过度表达。我们的初步数据表明，我们发现的 CMG2 拮抗剂（PGG、PGM）治疗可减少这些观察结果表明 CMG2 可能与发病率、生长和子宫内膜异位症相关的疼痛有关。治疗子宫内膜异位症相关疼痛的有用目标然而，我们对子宫内膜异位症的理解存在关键差距。 CMG2 生物学将减缓任何以 CMG2 作为目标的开发计划。第一个关键差距是细胞。其次，尚不清楚其靶向导致 CMG2 治疗后疼痛减轻的类型。子宫内膜异位症中 CMG2 信号传导的分子机制尚不清楚。 CMG2 靶向的功效和安全性尚不清楚。我们建议通过使用细胞类型特异性 CMG2 敲除小鼠来识别细胞类型来填补这些空白 CMG2 表达支持子宫内膜异位病灶的生长和疼痛，因为 CMG2 缺乏任何催化作用。域，我们通过差异蛋白相互作用追踪 CMG2 信号，然后，CMG2 在中的表达。接下来，我们将使用邻近蛋白质组学来确定人类病变中的适当细胞。与 CMG2 ± 抑制剂有差异相互作用的下游分子。然后，我们将使用 CRISPR 敲除和基于细胞的 CMG2 功能来确认信号传导。将使用特征良好、高通量的小鼠模型来评估 CMG2 靶向的安全性和有效性在整个离体和体内测定中，RNAseq 和 scRNAseq 将用于特异性 CMG2 抑制剂。识别 CMG2 阻断的转录特征，以验证体外测定并产生潜力 CMG2抑制剂的药效学标志物。完成拟议的工作将验证 CMG2 作为治疗子宫内膜异位症的靶点 - 它还将为子宫内膜异位症病理生理学提供重要见解，从而使子宫内膜异位症成为可能。产生治疗小说，并可能确定治疗该疾病的其他目标。此类药物将改善许多妇女的生活并减少使用阿片类药物来治疗这种疾病，从而改善许多人的生活。