Subproject for Endometriosis and Retinoids

    Project: Research project

    Project Details


    Endometriosis, the pathologic endometrium-like tissue on pelvic organs, develops and persists
    in part due to defective apoptosis and is associated with pelvic pain and infertility. During the
    previous funding period, we showed that retinoic acid (RA) induces endometrial expression of
    HSD17B2, an enzyme responsible for inactivating estradiol. Estradiol is a critical mitogen for
    endometriosis that is deficient of HSD17B2. A genome-wide gene expression profiling indicated
    strikingly lower expression of multiple RA-related genes in endometriotic tissue compared with
    matched endometrium: STRA6, a membrane receptor responsible for retinol (vitamin A) uptake,
    and CRABP2, which channels cytosolic RA to its nuclear receptor RARα to enhance apoptosis
    and reduce proliferation, were expressed at severely lower levels in endometriosis vs.
    endometrium. We find that these genes are primarily expressed in endometrial stromal cells and
    regulated by progesterone receptor (PR). We provide functional evidence that retinol and RA
    levels and expression of RA-target genes are significantly lower in endometriotic compared with
    endometrial stromal cells. Our overall hypothesis is that RA production and action is deficient in
    endometriosis compared with normal endometrium. This is responsible for deficient inactivation
    of estradiol and enhanced survival leading to persistence of endometriosis. The following aims
    will be pursued using established human and baboon experimental model systems of
    endometriosis. 1) To determine whether strikingly lower levels of STRA6 result in deficient RA
    production and action in endometriotic compared with normal endometrial stromal cells. We will
    test the hypothesis whether PR-dependent expression of STRA6 regulates retinol uptake
    leading to normal RA production in normal endometrial stromal cells, whereas reduced STRA6
    expression causes RA deficiency and enhanced survival in endometriotic stromal cells. 2) To
    define the pathologic consequences of CRABP2 deficiency in human endometriotic stromal
    cells. We will test the hypothesis whether CRABP2 is necessary for RA/RARα-dependent
    apoptosis and inhibition of proliferation in endometrial stromal cells, whereas in its absence, RA
    enhances cell survival via an alternative pathway. 3) To define the in vivo roles of the key
    genes for RA production and action in the baboon endometriosis model. We will test the
    hypothesis whether the key genes for RA production and RARα-targeted action are expressed
    in a cycle-dependent manner in normal endometrium and significantly reduced in eutopic
    endometrium of baboons with endometriosis and severely deficient in pelvic endometriotic
    implants, where cell survival is predominant.
    Effective start/end date7/1/156/30/20


    • National Institute of Child Health and Human Development (5R37HD038691-18)


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