Project?Summary? ? Embryo?implantation?failure?is?a?significant?causal?factor?of?infertility?for?women?worldwide.?Although?advances? in?our?understanding?of?oocyte?and?embryo?development?have?improved?pregnancy?success?rates,?these?rates? remain? unacceptably? low? due? in? part? to? an? endometrium? that? is? nonreceptive? to? the? embryo.? ? For? successful? implantation,? endometrial? receptivity? and? subsequent? decidualization? requires? coordinated? progesterone? (P4)? signaling? in? a? cell-?type? specific? manner.? ? While? the? signature? cellular? events? that? underpin? P4-?driven? uterine? receptivity? and? decidualization? are? known,? our? knowledge? of? the? pivotal? mediators? of? P4? action? in? these? processes? is? incomplete.? This? knowledge-?deficiency? is? significant? as? nothing? short? of? identifying? the? key? early? signals?that?underpin?P4-?driven?uterine?receptivity?will?address?the?current?clinical?limitations?in?diagnosing?and? treating? a? non-?receptive? uterus? at? the? molecular? level.? ? To? address? this? deficiency,? we? recently? demonstrated? that? the? promyelocytic? leukemia? zinc? finger? (PLZF)? transcription? factor? is? a? direct? target? of? the? progesterone? receptor? (PGR)? and? is? indispensable? for? P4-?dependent? decidualization? of?cultured? human? endometrial? stromal? cells? (hESCs).? As? further? translational? support? for? a? P4? mediator? role? for? PLZF? in? the? human? endometrium,? PLZF? expression? levels? in? human? endometrial? biopsies? are? significantly? induced? during? the? P4-?dominant? secretory?phase?of?the?human?non-?conception?menstrual?cycle.??In?the?early?pregnant?mouse,?Plzf?is?induced?in? the?epithelial?and?stromal?compartments?of?the?receptive?uterus?and?is?strongly?expressed?in?decidual?cells?with? pregnancy? progression.? These? findings? support? our? hypothesis? that? PLZF? (and? its? downstream? transcriptional? program)?acts?as?a?pivotal?mediator?of?P4-?dependent?uterine?receptivity?and?decidualization?and?does?so?in?an? endometrial? cell-?type? specific? manner.? This? hypothesis? will? be? tested? by? three? specific? aims.? Using? a? recently? generated?mouse?model?carrying?a?Plzf?conditional?allele,?Specific?Aim?1?will?establish?the?in?vivo?importance? of? Plzf? (and? its? transcriptional? programs)? in? P4-?dependent? endometrial? receptivity? and? decidualization.?? Dissecting?the?individual?contributions?of?epithelial?and?stromal?Plzf?signaling?in?the?murine?endometrium?during? the? periimplantation? period? will? be? a? major? focus? of? Specific? Aim? 2.? ? We? recently? demonstrated? that? direct? transcriptional? repression? of? the? early? growth? response? 1?(EGR1)? transcription? factor? by? PLZF? is? required? for? hESC?decidualization;??blocking?this?regulation?impairs?hESC?decidualization.??Prior?to?decidualization,?however,? EGR1?in?pre-?decidual?hESCs?is?required?for?these?cells?to?decidualize,?suggesting?that?EGR1??primes??the?pre-? decidual?hESC?for?decidualization.??Specific?Aim?3?will?address?this?proposal?by?molecularly?characterizing?the? P4-?PGR-?PLZF-?EGR1? regulatory? axis? that? is? required? for? in? vitro? and? in? vivo? decidualization.? ? These? aims? will? use? state-?of-?the-?art? engineered? mice? to? study? the? role? of? Plzf? in? endometrial? receptivity? and? decidualization? as? well? as? high? throughput? genome-?scale? approaches? to? identify? novel? endometrial? targets? directly? regulated? by? Plzf?and?the?transcriptional?interactome?through?which?this?regulation?occurs.? ?

R01HD042311

2002-04-01

2024-07-31