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:
  • 金额:
    $ 26.55万
  • 依托单位:
  • 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

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

项目成果

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MICHAEL SEAN ROGERS其他文献

MICHAEL SEAN ROGERS的其他文献

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{{ truncateString('MICHAEL SEAN ROGERS', 18)}}的其他基金

Functional requirement of CMG2 for endothelial cell chemotaxis and resulting angiogenesis
CMG2 内皮细胞趋化性和由此产生的血管生成的功能要求
  • 批准号:
    10522258
  • 财政年份:
    2022
  • 资助金额:
    $ 26.55万
  • 项目类别:
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
  • 批准号:
    10705085
  • 财政年份:
    2022
  • 资助金额:
    $ 26.55万
  • 项目类别:
Functional requirement of CMG2 for endothelial cell chemotaxis and resulting angiogenesis
CMG2 内皮细胞趋化性和由此产生的血管生成的功能要求
  • 批准号:
    10705632
  • 财政年份:
    2022
  • 资助金额:
    $ 26.55万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 26.55万
  • 项目类别:
Novel Angiogenesis Inhibitors Targeting the Anthrax Toxin Receptors
针对炭疽毒素受体的新型血管生成抑制剂
  • 批准号:
    7615664
  • 财政年份:
    2008
  • 资助金额:
    $ 26.55万
  • 项目类别:
Novel Angiogenesis Inhibitors Targeting the Anthrax Toxin Receptors
针对炭疽毒素受体的新型血管生成抑制剂
  • 批准号:
    8068796
  • 财政年份:
    2008
  • 资助金额:
    $ 26.55万
  • 项目类别:
Novel Angiogenesis Inhibitors Targeting the Anthrax Toxin Receptors
针对炭疽毒素受体的新型血管生成抑制剂
  • 批准号:
    8268448
  • 财政年份:
    2008
  • 资助金额:
    $ 26.55万
  • 项目类别:
Novel Angiogenesis Inhibitors Targeting the Anthrax Toxin Receptors
针对炭疽毒素受体的新型血管生成抑制剂
  • 批准号:
    8072400
  • 财政年份:
    2008
  • 资助金额:
    $ 26.55万
  • 项目类别:
Novel Angiogenesis Inhibitors Targeting the Anthrax Toxin Receptors
针对炭疽毒素受体的新型血管生成抑制剂
  • 批准号:
    7436075
  • 财政年份:
    2008
  • 资助金额:
    $ 26.55万
  • 项目类别:
Novel Angiogenesis Inhibitors Targeting the Anthrax Toxin Receptors
针对炭疽毒素受体的新型血管生成抑制剂
  • 批准号:
    7813810
  • 财政年份:
    2008
  • 资助金额:
    $ 26.55万
  • 项目类别:

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患有功能性腹痛疾病的青少年的睡眠结构被破坏
  • 批准号:
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  • 批准号:
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  • 财政年份:
    2022
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针对有功能性腹痛风险的幼儿进行基于互联网的预防干预的随机对照试验
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