PHYSIOLOGY OF RELAXIN-INSULIN-LIKE FACTORS

描述：（改编自申请人的描述）：最近的研究 表明哺乳动物胰岛素/松弛素蛋白家族由至少 至少6个成员，包括胰岛素、IGF-I、IGF-II和松弛素，以及 Leydig细胞来源的松弛素样肽（RLF或INSL 3）和早期的 胎盘胰岛素样肽（EPIL或INSL 4）。胰岛素和IGFs必不可少 有丝分裂、分化和血管生成的生长因子 细胞谱系松弛素主要由生殖组织产生， 发现对乳腺发育和子宫肌层活动很重要。 最近发现的RLF和EPIL已被证明主要由 性腺和胎盘。虽然已知胰岛素和IGFs介导 它们通过特定的受体，松弛素的假定受体， RLF和EPIL尚未分离。然而，孤儿受体（IRR： 与胰岛素受体相似的胰岛素受体相关受体 已经确定，这表明有其他配体属于 胰岛素/松弛素超家族。基于与成熟胰岛素的序列同源性 和松弛素，申请人分离了两种新的松弛素/胰岛素样因子 （RIF-1和RIF-2）。北方印迹杂交和免疫组织化学研究 RIFI可能参与睾丸功能的调节 而RIF-2可能在睾丸、肾脏、心脏和肾脏的功能中起作用。 个脑袋为了表征这些新型配体的功能重要性， 申请人建议使用标记的合成的 RIF多肽作为示踪物并鉴定天然成熟RIF蛋白 直接测序。这个实验有两个目的：1） 确定天然RIF蛋白的蛋白水解加工位点，和2） 产生大量成熟的RIF蛋白，用于表征 RIF受体。预计这项研究将导致 两个新的松弛素/胰岛素样配体的结构描绘 并为将来阐明其 生理功能。此外，从拟议的 实验将有助于诊断和治疗与疾病有关的疾病， 这些新的松弛素/胰岛素样因子的功能障碍。

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.