Although premature ovarian failure (POF) has been recognized as a cause of infertility for some time, the etiology of the disease remains undefined. An autoimmune cause in certain cases is suggested by several lines of evidence. POF has been associated with other autoimmune disorders: circulating antibodies to ovarian antigens have been demonstrated in the sera of women with POF, lymphocytic infiltrates have, on occasion, been observed in ovarian biopsies of some patients, immunosuppressive therapy has resulted in the return of normal ovarian function and autoimmune ovarian dysgenesis (AOD) can be induced experimentally in laboratory animals. The long-term objective of the proposed research is to define, from a functional standpoint, the genetically controlled regulatory mechanisms which govern the phenotypic expression of infertility associated with POF through the use of the murine model of day three thymectomy (D3Tx) induced AOD. It has been suggested that the immunoregulatory Ir mechanisms involved govern developmental processes associated with induction and maintenance of peripheral tolerance to the autoantigen which elicits the disease. In this study, a genetic approach will be utilized to identify and map the AOD susceptibility gene. This will be carried out using the AXB and BXA series of recombinant inbred strains (RIS) derived from the disease susceptible A/J strain (87% disease incidence) and the disease resistant C57BL/6J strain (8% disease incidence). Preliminary data using such mice indicate that the Ir locus controlling susceptibility is segregating among the RIS and that it may be linked to apolipoprotein A-1 (Apoa-1) on chromosome 9. Apoa-1 maps 2 cM from Thy-1, a cell surface antigen which purportedly plays a regulatory role in the functional maturation of follicles in normal adult ovaries. Confirmatory linkage analysis and precise mapping (a three-point cross) will be performed using the appropriate backcross population. The results of these studies will allow for: 1) an estimation of the number of independently segregating loci involved in controlling AOD; 2) the determination of genetic linkages, characterization of multiple inheritances, and investigation of the genetic reassortments involving AOD, and 3) the precise mapping of the Ir locus within the mouse genome, an absolute requirement for the long-term objective of cloning the gene. The Ir gene will also be genetically isolated by generating a C57BL/6J disease susceptible congenic strain. This approach will result in the establishment of a set of congenic mice which differ at the locus which controls disease susceptibility. Such animals will be invaluable for future studies on the biologic mechanisms controlling the phenotypic expression of disease susceptibility and/or resistance as well as in the development of therapeutic strategies for the early detection, prevention and/or treatment of POF.
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