The long term goal of this project is to understand the physiological mechanisms responsible for the onset of puberty in man. The proposed work will focus on the neurogenomics and structural hypothalamic remodeling underlying this fundamental event in human development. In higher primates, such as man and the rhesus monkey, puberty is delayed by a neurobiological """"""""brake"""""""" that holds pulsatile GnRH release, and, therefore activity in the pituitary-gonadal axis, in check until approximately 2-10 years of age depending on the species of primate. Although several apparently unrelated genes (NPY, TGFa, GPR54 and GAD 65 and 67) are implicated in this brake, a unifying molecular hypothesis for the onset of primate puberty has not been forthcoming. Similarly, although the postnatal primate hypothalamus exhibits neuronal plasticity, the significance of this structural remodeling in the pubertal resurgence of pulsatile GnRH release remains unclear. The present proposal will employ 2 general strategies. First, specific candidate genes will be examined in tandem with exploration of global developmental changes in hypothalamic gene expression in the rhesus monkey. Second the impact of blocking neuronal plasticity on the timing of the pubertal resurgence in pulsatile GnRH release will be examined. The following Specific Aims will be addressed:
Aim 1 - To determine the role of GPR54 signaling in regulating the central restraint and pubertal resurgence of pulsatile GnRH release.
Aim 2 - To determine whether inhibition of structural hypothalamic remodeling during juvenile development prevents the onset of gonadarche (puberty);
Aim 3 - To determine, in the absence of interfering testicular hormone feedback, the global profile of hypothalamic gene expression at the time of 1) the suppression of pulsatile GnRH release during infancy, and 2) the resurgence in pulsatile GnRH release at the end of the juvenile phase of development. The rhesus monkey will be used as an experimental paradigm. Standard physiological models will be used to examine whether increased GPR54 signaling will sustain precocious GnRH release. Structural remodeling will be prevented by intra-hypothalamic injection of endoneurominidase, and candidate and global gene expression will be examined by RNAse protection and hybridization to gene arrays containing 8,400 human cDNA's (or 8,000-10,000 monkey cDNA's), respectively.
Showing the most recent 10 out of 82 publications
