PHYSIOLOGY OF RELAXIN-INSULIN-LIKE FACTORS

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DESCRIPTION: (Adapted from applicant's description): Recent studies have shown that the mammalian insulin/relaxin family of proteins consists of at least six members including insulin, IGF-I, IGF-II, and relaxin, together with a relaxin-like peptide of Leydig cell origin (RLF or INSL3) and an early placenta insulin-like peptide (EPIL or INSL4). Insulin and IGFs are essential growth factors for mitogenesis, differentiation, and angiogenesis of diverse cell lineages. Relaxin, which is mainly produced by reproductive tissues, was found to be important for mammary gland development and myometrial activity. The recently identified RLF and EPIL have been shown to be mainly produced by gonads and placenta, respectively. While insulin and IGFs are known to mediate their actions through specific receptors, the putative receptors for relaxin, RLF and EPIL, have not been isolated. However, an orphan receptor (IRR: Insulin Receptor-related Receptor) showing similarity to the insulin receptor has been identified, suggesting that there are additional ligands belonging to the insulin/relaxin superfamily. Based on sequence homology to mature insulin and relaxin, the applicant has isolated two novel Relaxin/Insulin-like Factors (RIF-1 and RIF-2). Northern blot hybridization and immunohistochemical studies have shown that RIFI could be involved in the regulation of testis function whereas RIF-2 may have a role in the function of testis, kidney, heart, and brain. To characterize the functional importance of these novel ligands, the applicant proposes to establish RIF radioimmunoassys using a labeled synthetic RIF polypeptide as the tracer and to identify native mature RIF protein sequences through direct sequencing. This experiment has dual purposes: 1) to define the proteolytic processing sites of native RIF proteins, and 2) to produce large quantities of mature RIF proteins for characterizing the putative RIF receptors. It is anticipated that this study would lead to the delineation of the structure of two novel relaxin/insulin-like ligands derived from testis and provide the basis for future elucidation of their physiological functions. Additionally, knowledge gathered from the proposed experiments would help the diagnosis and treatment of diseases associated with the dysfunction of these novel relaxin/insulin-like factors.