IMPAIRED SOMATOMEDIN RESPONSIVENESS AND GROWTH FAILURE

在我的儿科内分泌学博士后培训期间 后来在纽约大学担任助理教授的经历 加州大学旧金山分校(UCSF)，我已经开发了 对儿童发育障碍有主要兴趣， 特别是，涉及生长激素调节的因素 (GH)和GH依赖的胰岛素样生长因子(IGFS)或 生长抑素(Sm)。政府间气候变化框架已被证明具有重要作用 在出生后的躯体生长中，也被牵连到 对胎儿生长的调节。由于IGF通过以下方式发挥其作用 它与特定的细胞表面受体相互作用， 假设受体缺陷可能导致胰岛素样生长因子受损 反应迟钝，并因此成为增长失败的原因。上一首 对患有IGF-I受体缺陷的儿童进行鉴定的尝试 利用受体的竞争结合研究和测量 反应性，并提示IGF-I受体缺陷构成 一组不同的疾病。 在资助期内要完成的具体目标有 旨在研究肌动蛋白的合成和调控。 IGF-I受体在分子水平上，包括以下内容： (1)筛选人胰岛素样生长因子-I受体基因 基于人工合成寡核苷酸探针的cDNA文库 已发表的c DNA序列；(2)将该c DNA用作IGF-I的探针 用稳态信使核糖核酸水平检测受体基因的表达 生长障碍儿童的成纤维细胞；(3)与 MRNA水平与a)125I-IGF-I结合、b)受体的测定 使用抗IGF-1的特异性单抗进行生物合成 I受体和c)IGF-I诱导的氨基异丁酸摄取和 生长发育儿童成纤维细胞的胸腺嘧啶核苷掺入 紊乱；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、 IGF-I受体基因上的甲状腺激素、IGF-I和胰岛素 在正常人成纤维细胞中表达。 这些研究将在被转介到 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·格兰巴赫博士和 塞尔娜·卡普兰。将进行细胞和分子研究 在艾拉·戈德费恩博士的指导下 山上的实验室锡安医院，加州大学旧金山分校的附属医院。这些 生物化学研究可能有助于进一步了解其作用。 IGF-I受体在正常和异常生长中的表达。

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.