Molekulare Ursachen der IGF1 Resistenz beim Menschen

人类 IGF1 抵抗的分子原因

• 批准号: 47079552
• 负责人: Professor Dr. Roland Pfäffle
• 金额: --
• 依托单位: Klinik und Poliklinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/47079552?language=en
• 关键词: Molekulare; Ursachen; der; IGF1; Resistenz

Three percent of all neonates are born small for gestational age (SGA) and about 15% of them fail to catch up height. Being born SGA entails multiple adverse consequences ranging from increased perinatal mortality, psychosocial or mental problems, up to unfavorable effects in adulthood. Somatic growth is regulated by a strong genetic component yet the etiology of most SGA patients has to be regarded as idiopathic. Results from the ongoing project have provided evidence that a significant fraction of SGA patients are carriers of genetic aberrations affecting genes of the IGF hormone – receptor system. New findings comprise the identification of 9 novel IGF1R mutations including the first homozygous amino acid substitution, the first detection for a putative pathogenic IGF2 point mutation as well as the identification of a putative SGA susceptibility region. These results corroborate our hypothesis relying on published information from animal models that SGA of a large fraction of patients, particularly if presenting with IGF1 resistance, is caused monogenic disruptions. Studies to analyze aberrations of cytoplasmic molecules that transmit the hormonal signal inside the cell will enter the focus of the project applied herein. Moreover, the more detailed clinical, genetic, and molecular biological characterization of the aforementioned mutations will provide the fundament for specific analytical future studies. The identification of human mutations causing SGA and unraveling underlying mechanisms allows a precise functional assignment of molecules of the IGF system in a whole-body setting. Due to the pleiotropic actions of the IGF system important implications for a specific treatment of growth disorders, but also cancer as well as metabolic and neurodegenerative diseases can be expected.

3%的新生儿出生时小于胎龄儿（SGA），其中约15%的新生儿无法赶上身高。出生SGA会带来多种不良后果，从围产期死亡率增加，心理或精神问题，到成年期的不利影响。躯体生长受强遗传成分调节，但大多数SGA患者的病因必须被视为特发性。 正在进行的项目的结果提供了证据表明，相当一部分SGA患者是影响IGF激素受体系统基因的遗传畸变的携带者。新发现包括鉴定9种新型IGF1R突变，包括第一个纯合氨基酸取代，第一次检测到推定的致病性IGF2点突变以及鉴定推定的SGA易感区域。这些结果证实了我们基于动物模型已发表信息的假设，即很大一部分患者的SGA，特别是如果表现出IGF1耐药性，是由单基因破坏引起的。 分析细胞内传递激素信号的细胞质分子畸变的研究将成为本文所应用项目的重点。此外，更详细的临床，遗传和分子生物学特征的上述突变将提供具体的分析未来的研究基础。 鉴定导致SGA的人类突变并解开潜在机制允许在全身环境中对IGF系统的分子进行精确的功能分配。由于IGF系统的多效性作用，可以预期对生长障碍的特定治疗的重要意义，而且还可以预期癌症以及代谢和神经退行性疾病。