Mechanisms of Adrenal Differentiation

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

PROPOSAL ABSTRACT The long range objective of our laboratory is to understand the cellular and molecular mechanisms by which signaling pathways and downstream transcription factors coordinate the specification of adrenocortical cells within the adrenal gland. Our strategy for this proposal is to focus on the role of SF1 and the SF1 target gene Dax1 in the regulation of adrenocortical growth maintenance. Based on our preliminary data, we hypothesize that unique transcriptional programs in subcapsular undifferentiated progenitor cells serve to maintain the functional capacity of the adrenal cortex. Our specific aims are directed towards a systematic characterization of novel functions of SF1 critical to this process. We propose to determine the origin of the SF1 positive subcapsular cells (specific aim 1), define the role of Dax1 in the self-renewal and multipotent properties of these adrenocortical cells in vivo (specific aim 2) and determine the mechanisms by which SF1 is activated to initiate a unique proliferation-associated transcriptional profile in this subcapsular population (specific aim 3). The studies proposed here will provide the critical framework for understanding the role of SF1 in adrenocortical stem/progenitor cells in adrenal growth maintenance and lay the groundwork for future therapeutic efforts in diseases of adrenal growth including both hypoplasias and cancer.