IMPAIRED SOMATOMEDIN RESPONSIVENESS AND GROWTH FAILURE

在我的儿科内分泌学博士后培训期间， 随后的经验，作为一个开始助理教授在 加州旧金山弗朗西斯科（UCSF），我已经开发和 对儿童期生长障碍的主要兴趣， 特别是参与生长激素调节的因子 (GH)和GH依赖性胰岛素样生长因子（IGFs）或 生长调节素（Sm）。 IGFs已被证明具有重要作用 在出生后的身体生长，也有牵连， 调节胎儿生长。 由于IGFs通过以下方式发挥作用： 与特定的细胞表面受体相互作用， 假设受体缺陷会导致IGF受损， 反应能力，从而成为生长失败的原因。 先前 鉴定IGF-I受体缺陷儿童的尝试 利用竞争性结合研究和受体的测量 反应性，并表明IGF-I受体缺陷构成 一组不同种类的疾病 在资助期内要达到的具体目标是 针对合成和调节的研究， IGF-I受体在分子水平上，包括以下几个方面： (1)通过筛选人IGF-I受体，鉴定IGF-I受体的cDNA， cDNA文库与合成寡核苷酸探针的基础上， （2）将该cDNA作为IGF-1的探针 受体基因表达，通过测量稳态mRNA水平， 来自生长障碍儿童的成纤维细胞;（3）与 mRNA水平，测量a）125 I-IGF-I结合，B）受体 使用针对IGF-1的特异性单克隆抗体进行生物合成。 c）IGF-I诱导的氨基异丁酸摄取， 生长期儿童成纤维细胞胸苷掺入 疾病;和（4）表征激素因素的影响 已知会影响生长，包括糖皮质激素，性类固醇， 甲状腺激素、IGF-I和胰岛素对IGF-I受体基因的影响 在来自正常受试者的成纤维细胞中表达。 这些研究将在儿童中进行， 儿科内分泌服务，一个主要的转诊中心， 儿童生长障碍，由梅尔文·格伦巴赫博士监督， 塞尔娜·卡普兰 将进行细胞和分子研究 在细胞生物学部的伊拉戈德芬博士的监督下 实验室在山。加州大学旧金山分校附属锡安医院 这些 生物化学研究可能会导致进一步了解，f的作用， IGF-I受体在正常和异常生长中的作用。

During my Post-doctoral training in Pediatric endocrinology and subsequent experience as a starting assistant professor at the University of California San Francisco (UCSF), I have developed and pursued a primary interest in growth disorders of childhood, and in particular, factors involved in the regulation of growth hormone (GH) and the GH-dependent insulin-like growth factors (IGFs) or somatomedins (Sm). IGFs have been shown to have an important role in post-natal somatic growth, and have also been implicated in the regulation of fetal growth. Since IGFs exert their effects by interacting with specific cell-surface receptors, it is hypothesized that a receptor defect could result in impaired IGF responsiveness and thus be a cause of growth failure. Previous attempts to identify children with IGF-I receptor defects have utilized competitive binding studies and measurements of receptor responsiveness, and suggest that IGF-I receptor defects constitute a heterogeneous group of disorders. The specific goals to be accomplished during the grant period are directed towards the study of the synthesis and regulation of the IGF-I receptor at the molecular level, and include the following: (1) to identify a cDNA for the IGF-I receptor by screening a human cDNA library with synthetic oligonucleotide probes based on the published cDNA sequence; (2) to use this cDNA as a probe of IGF-I receptor gene expression by measuring steady state mRNA levels in fibroblasts from children with growth disorders; (3) to correlate mRNA levels with measurements of a) 125I-IGF-I binding, b) receptor biosynthesis using a specific monoclonal antibody against the IGF- I receptor, and c) IGF-I induced aminoisobutyric acid uptake and thymidine incorporation in fibroblasts from children with growth disorders; and (4) to characterize the effects of hormonal factors known to influence growth, including glucocorticoids, sex steroids, thyroid hormones, IGF-I, and insulin, on IGF-I receptor gene expression in fibroblasts from normal subjects. These studies will be carried out in children referred to the pediatric endocrinology service, a major referral center for childhood growth disorders, supervised by Drs. Melvin Grumbach and Selna Kaplan. Cellular and molecular studies will be carried out under the supervision of Dr. Ira Goldfine in the Cell Biology Laboratory at Mt. Zion Hospital, a UCSF affiliate. These biochemical studies may lead to further understanding ,f the role of the IGF-I receptor in normal and abnormal growth.