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Identification of a Novel Target for the Treatment of Endometriosis-associated Pain

确定治疗子宫内膜异位症相关疼痛的新靶点

基本信息

批准号：
10508963
负责人：
MICHAEL SEAN ROGERS
金额：
$ 26.55万
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：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10508963
关键词：
ARNT gene Abdominal Pain Affect Affinity Agonist American Arrestins Biological Assay CD59 Antigen Cells Chronic Disease Clinical Research Data Development Disease Drug Kinetics Drug Targeting Endometrium Estrogen Receptors Exhibits FDA approved Family Female of child bearing age Fiber Friends Functional disorder G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Gene Expression Gene Expression Profile Genes Growth Health Care Costs Hemosiderin Hormonal Human Human Genome Immune Infertility Inflammatory Knockout Mice Knowledge Laboratories Lead Lesion Libraries Lipids Measures Mediating Mediator of activation protein Methodology Modeling Molecular Non-Steroidal Anti-Inflammatory Agents Operative Surgical Procedures Pain Patients Pelvic Pain Pharmaceutical Preparations Program Development Property Publishing Receptor Cell Regimen Resources Sampling Signal Transduction Stimulus Structure Sum Surveys System Testing Therapeutic Tissues Up-Regulation Validation Woman Work antagonist cell type child bearing chronic pelvic pain cost cost estimate endometriosis experience experimental study follow-up high throughput screening human disease in vivo knock-down lipid mediator mouse model new therapeutic target novel novel therapeutics overexpression pain relief pharmacodynamic biomarker pharmacophore preclinical study receptor receptor expression screening side effect single-cell RNA sequencing success therapeutic development tool unpublished works

项目摘要

Endometriosis is an inflammatory disease characterized by the presence of endometrium-like lesions and progressive abdominal or pelvic pain. It affects ~10% of women of childbearing age and ~30% of patients are not effectively treated by existing options; new therapeutics are desperately needed. We have developed and validated a mouse model of endometriosis pain. Using that model, we discovered that the specific pro- resolving lipid mediator (SPM) protectin DX (PDX) rapidly abolishes endometriosis-associated pain and shrinks lesions. Unfortunately, poor stability and pharmacokinetic properties render PDX a poor drug lead. To leverage the anti-endometriosis activity of PDX, its receptor must be identified. All SPMs for which a high affinity receptor is known activate G-protein coupled receptors (GPCRs). Thus we hypothesize that PDX acts through a GPCR and aim to identify it and the cell type(s) expressing the PDX receptor. We will identify the mechanism by which protectin DX acts by using the PRESTO-Tango system to measure arrestin activation in a comprehensive library of human non-olfactory GPCRs. We will then identify the G-protein(s) that couple to this GPCR in the context of PDX signaling. To confirm that this is the relevant receptor, we will measure the effect of ablating this GPCR on the PDX-mediated increase in efferocytosis and up regulation of M2 markers in RAW264.7 cells. Next, we will seek to identify the cell types that mediate the anti-endometriosis effects of multiple SPMs, including MaR1, RvD5, and PDX. To that end, we will use single- cell RNAseq (scRNAseq) to identify cell types that express SPM receptors in our mouse model of endometriosis-associated pain at a relevant timepoint. We will also measure the effect of PDX on the transcriptional profile of relevant cell types in vivo, in order to begin to understand how PDX relieves pain and reduces lesion size. Then, we will use available resources to confirm expression of these receptors in cells human lesions. When these experiments are complete, we will have identified a novel, druggable target for endometriosis therapy. As this is expected to be a GPCR, common strategies like high-throughput screening (with which we have experience) can then be used to identify pharmacophores that lack the liabilities present in PDX, itself. We will also identify pharmacodynamic markers of protectin DX activity that will allow target engagement to be measured during a therapeutic development program. Although additional target validations work (e.g. with knockout mice) will remain, these studies will provide important knowledge about the mechanism by which SPMs, including PDX, reduce endometriosis-associated pain and lesion growth. Thus, the knowledge to be gained by these studies will represent an important advance toward the development of desperately needed novel therapeutics for endometriosis.

子宫内膜异位症是一种炎症性疾病，其特征是存在子宫内膜样病变和