Manyorgansarecapableofextensiverepairafterdamage,byknownmechanismsthatcanbeexploitedclinically. By contrast, in spite of the central importance of the ovary for human fertility and women?s health, many importantaspectsofitsbasicbiology,includingitscapacityforrepair,arepoorlyunderstood.Forexample,ovarian longevity is dependent on the supply of follicles, but how the balance between quiescent versus developing follicles is regulated has not yet been determined. Likewise, it was recently discovered that adult and fetal granulosa cells arise at independent stages from LGR5+ progenitors in the neonatal ovarian surface epithelium (OSE) -? but whether these LGR5+ cells can renew adult follicles is not known. Finally, in many organs, vascular, neuronal, and immune cells play critical roles in repair, but their functions in the ovary have not been fully investigated. We recently developed a novel murine model of chemotherapy (CTx)-?induced infertility and prematureovarianfailure(POF).Surprisingly,whenwegraftedafragmentofanormalovarytooneovaryofaCTx-? treatedfemale,graftedfemalesproducedmultiplelittersoverthenext5months,containingnormalpupsderived from both the host and the donor. Histology revealed that only the grafted ovary was rescued, while the contralateralsidedegeneratedandallfollicleswerelost.Theseexperimentsshowthattheovarycanberescued after CTx through signals from a normal ovary. The primary goals of this project are to characterize the mechanisms underlying the loss of all follicles after CTx, and to determine how a small graft from a healthy ovary rescues the host organ system. Our experiments are designed to test three alternative, or complementary, mechanisms of rescue. First, preliminary results suggest that it is the rapidly dividing granulosa cellsingrowingfollicles,andnotoocytes,thataretheprimarytargetofDNA-?damagingchemotherapeuticdrugs.
In Aim 1 we will test whether the loss of granulosa cells in growing follicles leads to de-?repression of quiescent granulosacellsinprimordialfollicles,resultinginexhaustionofthereservepoolor?follicleburnout?,andwhether signals from the graft block this depletion.
In Aim 2, we will test whether LGR5+ cells in the OSE respond to damageandgiverisetonewgranulosacellsaftergrafting.CTxmayinterferewiththisregenerativeactivitywhile signals from the graft may promote it.
In Aim 3, we will test whether the graft enhances signals from neural, vascular,orimmunecellsthatcanpromoterepairafterinjury.Resultsmayleadtonewtherapiesandchangethe prognosisforwomenundergoingPOFfromdifferentcauses.
Inthelastfewdecades,significantadvancesinchemotherapy(CTx)treatmentshaveledtoanincrease inpatientsurvival.However,afrequentsecondaryeffectofCTxinyoungwomenisprematureovarian failure (POF), resulting in infertility and early-?onset menopause. Our recent results indicate that it is possibletorescuetheovaryfromtheeffectsofCTx,butthebiologyunderlyingtheabilityoftheovary torecoverafterCTxdamageisnotunderstood.Identificationofthemechanism(s)ofrescuepromisesto revealnovelbiologyoftrophicinteractionsbetweendifferentcellpopulations,includingprogenitorcells, intheovary.Thishasthepotentialfortherationaldesignoftreatmentsthatwillimprovethequalityof lifeofmillionsofwomenandtheirfamilies.