Physiologic Role of the Somatotroph IGF-1 Receptor

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DESCRIPTION (provided by applicant): The growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis plays a key role in the control of human growth and alterations in this axis usually result in growth retardation. GH synthesis and secretion by the anterior pituitary somatotrophs is under the control of stimulatory GH releasing hormone (GHRH) and inhibitory somatostatin (SST) from the hypothalamus. Many of the actions of GH are mediated by the stimulation of production of IGF-1. Although IGF-1 has been shown to have negative feedback effects on the somatotroph cell, the exact physiologic mechanism of GH regulation is unknown. In order to increase our understanding of the central feedback role of IGF-1 on somatotroph regulation, the goal of this proposal is to create a knockout mouse that lacks the IGF-1 receptor (IGF-1 R) on the somatotroph. Specific Aim #1 will involve creating the knockout animal using the cre/lox system; animals that contain loxP sites at the IGF-1 R locus will be mated with mice bearing the rGHpCre recombinase transgene. Careful documentation of the genotype and confirmation of effective recombinase activity (immunocytochemistry for GH and IGF-1 R), along with auxiologic parameters documenting growth and development as well as measurements of hormone levels will be performed with the somatotroph-specific IGF-1 receptor knockout (SIRK) and control mice. Specific Aim #2 is designed to provide evidence of the neuroendocrine role of IGF-1 feedback using provocative testing for the release of hypothalamic factors, human growth hormone releasing hormone (GHRH) and somatostatin. In addition, in order to gain some insight into the molecular mechanisms involved in negative feedback of IGF-1, quantitative reverse-transcriptase PCR will be performed to determine mRNA levels of IGF-1 target genes. These studies will provide definitive in vivo evidence of the role of negative feedback of IGF-1 to the somatotroph and its relative importance in control of somatotroph function with respect to the neuroendocrine factors, GHRH and somatostatin. This design will also give insight into the contribution of IGF-1 in hypothalamic feedback in the control of somatotroph function. Relevance to public health: Despite medical advances in the treatment of growth disorders with GH and IGF-1, a clear understanding of their relative contributions to somatic growth and the mechanisms of action remain elusive. This proposal aims to perturb this system to study the associated changes in growth and hormone secretion; therefore providing better insight into the regulation of normal and abnormal growth. In the future, this may provide the basis for guidelines for the evaluation and treatment of children with growth disorders.