Inhibin/Activin Family in Human Cranifocial Development

抑制素/激活素家族在人类颅骨发育中的作用

• 批准号: 6485761
• 负责人: Geralyn Mary Messerlian
• 金额: $ 6.97万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6485761
• 关键词: cleft palate; clinical research; craniofacial; developmental genetics; disease /disorder etiology; embryo /fetus; gene environment interaction; gene expression; genetic regulation; genetic susceptibility; growth /development; hormone receptor; hormone regulation /control mechanism; human genetic material tag; human tissue; immunocytochemistry; immunologic assay /test; inhibin; intermolecular interaction; mammalian embryology; molecular pathology; polymerase chain reaction; postmortem; protein localization; protein structure function; radiotracer

The etiology of craniofacial abnormalities is multi-factorial and defects such as cleft palate often occur in the absence of a known cause. Compelling data suggest that inhibin/activin family of proteins is critical for normal craniofacial development and that aberrant production or action of these proteins may have a role in craniofacial defects. Transgenic mice lacking the inhibin/activin betaA gene had severe craniofacial abnormalities that prevented suckling in the pups and led to perinatal death. Knock-out of follistatin also resulted in palate abnormalities, and a subset of mice lacking an activin receptor had skeletal and facial abnormalities similar to that of the human Pierre-Robin syndrome. While activin (beta/beta dimer) was discovered on the basis of its reproductive functions, we now know that this protein, a member of the TGF-beta superfamily, serves as a regulator of growth and differentiations in a variety of cell systems. In particular, activin is critical for mesoderm induction in Xenopus, and activin and follistatin are important in the development and metabolism of bone, a tissue critical for palate formation. Inhibin/activin/follistatin proteins and genes are expressed in a wide spectrum of human fetal tissues. Our preliminary data show that activin protein and activin receptors are present in the developing human fetal palate. Based on these findings, we hypothesize that the inhibin/activin family has a critical role in normal human craniofacial development and that craniofacial malformations can result from deficient production or activity of one or more of these proteins. Since this family has not yet been studied in human craniofacial tissues, the first aim is to elucidate the temporal and regional localization and expression of the inhibin and activin subunits, follistatin and activin receptors throughout normal human craniofacial development using autopsy tissues collected from embryonic through neonatal ages. The second aim is to determine whether alterations in mRNA expression, protein biosynthesis, or protein actions for activin, follistatin or activin receptors are associated with cleft palate in humans by comparison with gestational age-matched normal palate tissues. The long term goals of this project are to study the underlying mechanism(s) by which the inhibin/activin family of proteins may lead to craniofacial malformations such as cleft palate, and ultimately to devise a prenatal treatment that may prevent or reverse the malformation.

颅面畸形的病因是多因素的，并且缺陷例如腭裂通常在没有已知原因的情况下发生。令人信服的数据表明，蛋白质的Escherubin/激活素家族对于正常颅面发育至关重要，并且这些蛋白质的异常产生或作用可能在颅面缺陷中起作用。 缺乏Escherichin/activin betaA基因的转基因小鼠， 严重的颅面畸形， 并导致围产期死亡。卵泡抑素的敲除还 导致腭异常，而一组缺乏 活化素受体有骨骼和面部异常， 人类的皮埃尔-罗宾综合征 虽然激活素（β/β二聚体）是在其基础上发现的， 生殖功能，我们现在知道这种蛋白质， TGF-β超家族的一员，作为生长调节剂， 在各种细胞系统中的分化。特别是，激活素 是非洲爪蟾中胚层诱导的关键，而激活素和 卵泡抑素在发育和代谢中起重要作用， 骨是腭形成的关键组织 抑制素/激活素/卵泡抑素蛋白质和基因在一个或多个细胞中表达。 广泛的人类胎儿组织。 我们的初步数据表明，激活素蛋白和激活素 受体存在于发育中的人胎儿腭中。基于这些研究结果，我们假设，在正常的人类颅面发育和颅面畸形，可能会导致一个或多个这些蛋白质的生产或活动不足的factorbin/激活素家族具有关键作用。由于这个家庭还没有在人类颅面组织中进行研究，第一个目的是阐明的时间和区域的定位和表达的follicin和激活素亚基，卵泡抑素和激活素受体在整个正常的人类颅面发育使用尸检组织从胚胎到新生儿年龄收集。第二个目的是通过与胎龄匹配的正常腭组织比较，确定激活素、卵泡抑素或激活素受体的mRNA表达、蛋白质生物合成或蛋白质作用的改变是否与人类腭裂相关。该项目的长期目标是研究潜在的机制，通过该机制，蛋白质的Escherobin/activin家族可能导致颅面畸形，如腭裂，并最终设计出一种产前治疗，可以预防或逆转畸形。