R01 HD037096-11A1: Inhibin actions on reproductive target tissues
The objective of this research is to understand the structural determinants that influence inhibin heterodimer assembly, processing and antagonism of an activin signal. The most recognized action of inhibin is to suppress FSH production and secretion by the pituitary gonadotrope in vitro and in vivo. Inhibin levels are regulated during the reproductive cycle to ensure normal FSH-dependent follicle recruitment. Recent work points to a broader role for inhibin in bone metabolism, regulation of adiposity and as a marker of fetal disease. Little is known regarding the structure-function relationships that evolved to create the only antagonist pair of ligands in the TGFβ superfamily and why no other antagonists emerged over evolutionary time. Understanding the underlying structural features of inhibin will permit a better understanding of its ability to function as an endocrine hormone and as an activin antagonist.
Inhibin is a dimeric glycoprotein consisting of two subunits (α- and either βA or βB) that form isomers called inhibin A and inhibin B. The ovarian granulosa cell produces both ligands, whereas inhibin B is the dominant form produced by the Sertoli cells. Loss of inhibins at the time of menopause in women, following Sertoli damaging chemotherapy in men, or by experimental interventions leads to a prodigious increase in FSH production, indicating that these ligands are central to FSH restraint in an endocrine manner. We have shown that the cellular machinery that regulates inhibin biosynthesis and processing is important to inhibin action and now hypothesize that biological regulation of inhibin is encoded in the primary and tertiary structure of the hormone and that these protein codes can be solved both functionally and at the structural levels. Toward this end, we now have crystals of inhibin with its binding receptor (ActRIIB) and the inhibin binding domain of betaglycan (tZP). This is an exciting development. This work is essential to our understanding of the biological activity of this ligand, and can be instructive regarding the development of new antagonistic biologics that can control other members of the TGFβ superfamily. There are three interrelated experimental aims in this proposal that will address the central hypothesis. The aims rely on sophisticated and innovative biochemical, cell biological, biophysical, and structural methods. These studies are expected to provide insight into the control of inhibin action and to a more complete understanding of normal fertility and the mechanisms that underlie reproductive diseases in women resulting from inappropriate hormone action.