EXTRACELLULAR MATERIALS AND EMBRYONIC ORGAN FORMATION

细胞外物质和胚胎器官的形成

• 批准号: 6054708
• 负责人: MERTON R BERNFIELD
• 金额: $ 36.27万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6054708
• 关键词: biological signal transduction; body weight; extracellular matrix; gene expression; genetic mapping; hypothalamus; laboratory mouse; nutrient intake activity; nutrition related tag; obesity; protein protein interaction; receptor expression; syndecan

DESCRIPTION (adapted from investigator's abstract): Syndecans, cell surface heparan sulfate proteoglycans, (HSPG) bind and modulate the activity of a large number of extra-cellular effectors. The ectodomains of the syndecans can be shed, generating soluble HSPGs that can inhibit these cell surface interactions. Several transgenic mouse lines that express high levels of cell surface syndecan- 1 under the control of a CMV promoter/enhancer were generated to evaluate its functions in vivo. Syndecan- 1 was expressed in multiple somatic tissues and in the hypothalamic areas that regulate body weight. The transgenic mice mimic (i) obese mice with abnormalities in melanocortin-4 receptor function and (ii) humans with the Bardet-Biedl syndrome, a genetic malformation and obesity syndrome of unknown etiology. Transgenic expression of syndecan- 1 appears to have has uncovered a physiological control of feeding behavior. These studies define new functions for syndecans and have important implications for understanding eating disorders, both obesity and cachexia. Obesity is a significant public health hazard; about half of U.S. women and men are now considered overweight and the IOM indicates that this costs more than $70 billion annually in the U.S. Thus, syndecan induction and syndecan interactions are potentially important new targets for pharmacological control of body weight. Specifically, the investigators aim to explore the remarkable phenotypes produced by syndecan- 1 overexpression: (i) establish the role of syndecans in melanocortin receptor function by characterizing the interaction of syndecans with agouti/AGRP peptides and analyzing how this interaction modulates melanocortin receptor signaling both in vitro and in vivo. (ii) evaluate whether hypothalamic expression of syndecan-3 is a physiological regulator of feeding behavior by characterizing the induced expression of hypothalamic syndecan-3. analyzing feeding behavior in syndecan-3 null mice and identifying potential regulators of hypothalamic synce~an-3 expression. (iii) analyze the obesity and morphogenetic abnormalities of the syndecan- 1 overexpressing mouse by evaluating the mouse as a genetic model of the Bardet-Biedl syndrome and by identifying the genes responsible for morphogenetic abnormalities and for reducing the obesity.

描述（改编自研究者摘要）：Syndecans，细胞表面 硫酸乙酰肝素蛋白聚糖（HSPG）结合并调节大的 细胞外效应物的数量。多配体蛋白聚糖的胞外域可以是 脱落，产生可溶性HSPGs，可以抑制这些细胞表面 交互.表达高水平细胞凋亡的几种转基因小鼠系 在CMV启动子/增强子的控制下产生表面多配体蛋白聚糖-1 以评价其在体内的功能。多配体蛋白聚糖-1在多个 体细胞组织和调节体重的下丘脑区域。的 转基因小鼠模拟（i）黑皮质素-4异常的肥胖小鼠 受体功能和（ii）人类与Bardet-Biedl综合征，遗传 畸形和病因不明的肥胖综合征。的转基因表达 syndecan- 1似乎揭示了进食的生理控制 行为 这些研究定义了syndecans的新功能，并具有重要意义。 对理解饮食失调，包括肥胖和恶病质的影响。 肥胖是一个重大的公共健康危害;大约一半的美国女性和男性 现在被认为超重，IOM表示， 在美国每年有700亿美元。因此，syndecan诱导和syndecan 相互作用是药理学控制的潜在重要新靶点 体重。具体来说，研究人员旨在探索显着的 多配体蛋白聚糖-1过表达产生的表型：（i）确定 多配体聚糖在黑皮质素受体功能中的作用 与agglutamine/AGRP肽的多配体蛋白聚糖的相互作用，并分析这种相互作用如何 在体外和体内调节黑皮质素受体信号传导。（二） 评估下丘脑syndecan-3的表达是否是一种生理性的 通过表征诱导表达的摄食行为调节剂 下丘脑多配体蛋白聚糖-3。分析syndecan-3缺失小鼠的进食行为， 鉴定下丘脑synce~an-3表达的潜在调节因子。（三） 分析肥胖和syndecan- 1的形态发生异常， 通过评估小鼠作为过表达小鼠的遗传模型， Bardet-Biedl综合征，并通过确定基因负责 形态发生异常和减少肥胖。