A combinatorial approach using steroidgenic factor-1 (SF-1, NR5A1) to elucidate novel mechanisms in adrenal and reproductive biology. (360G-Wellcome-079666_Z_06_Z)

We aim to elucidate novel molecular mechanisms involved in human adrenal and reproductive development, and to relate these findings to patients with disorders of adrenal and reproductive function and to variations within normalpopulations. Using microarray and proteomic approaches, we now have the capacity to identify many of the components involved in these systems: the challenge is to focus on those factors relevant to human disease. We will address this using a combinatorial approach (Aims 1-3). In Aim 1, key differentially expressed genes/proteins will be identified in the adrenal, testis and ovary at critical stages of human development between 6-12 weeks gestation. In Aim 2, a subset of important novel genes will be identified by manipulation of the pivotal nuclear receptor sterodiogenic factor-1 (SF-1). InAim 3, genetic loci containing potentially important genes will be mapped using "literature mining" techniques and array analysis of patients with adrenal and reproductive disorders. Taken together, these studies will provideinsight into important biological mechanisms of development and function. Analysis of candidate factors in patients/families with adrenal and reproductive disorders will define novel endocrine syndromes and should identify key factors important in milder clinical phenotypes or physiological variability within a "normal" population (Aim 4).