ROLE OF MORPHOGENETIC PROTEINS IN EMBRYOGENESIS AND TISSUE REGENERATION

形态发生蛋白在胚胎发生和组织再生中的作用

• 批准号: 5200772
• 负责人: M MOOS
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5200772
• 关键词: Xenopus; articular cartilage; bone regeneration; cartilage; complementary DNA; developmental genetics; embryogenesis; gene expression; gene induction /repression; growth factor; in situ hybridization; molecular cloning; nonmammalian vertebrate embryology; osteogenesis; polymerase chain reaction; protein sequence

During the past year, we have characterized five genes related to the bone morphogenetic protein family of growth factors. These proteins are emerging as key determinants in the specification of positional information during embryogenesis and have assumed importance to the biotechnology community owing to their almost certain therapeutic utility in a variety of clinical contexts, including nonunion fractures and other orthopedic and reconstructive indications, alveolar ridge augmentation, and other types of tissue repair. One of these , Anti-Dorsalizing Morphogenetic Protein (ADMP), exerts profound effects on the anatomic pattern of the entire embryo. Though it is expressed in the embryonic region associated with induction of dorsal and neural structures, it profoundly suppresses them when overexpressed. ADMP is the only such growth factor identified so far. Because its expression is increased in response to manipulations that produce exaggerated dorsal structures, we propose that the protein acts as a feedback system that moderates the effects of naturally occurring dorsalizing signals in vivo. Two members of a distinct subfamily of these growth factors, originally identified in Xenopus genomic DNA and then characterized in collaboration with Dr. Frank Luyten of NIDR, have been implicated in patterning of the developing vertebrate limb by hybridization in situ and genetic studies in mammals. These genes, termed Cartilage-Derived Morphogenetic Proteins (CDMPs) are expressed only in cartilage, and are thus the only growth factors known that are specific for this tissue. We have also isolated a homolog of mammalian Osteogenic Protein-1 (OP-1). This gene demonstrates a complex and dynamic expression pattern (ventral endoderm/mesoderm, eye, ear vesicle, pituitary, pineal, neural axis, and branchial arches, suggesting several distinct roles during embryogenesis. Overexpression of the gene causes induction of ventral markers and pronounced proliferation of ventral tissue. A partial cDNA clone for another novel member of the BMP family has been isolated from Xenopus. This gene is expressed during gastrulation in the animal region of the embryo; its biological activities remain to be identified. Finally, sequence from a novel protein isolated from bovine articular cartilage has been used to isolate the corresponding gene, which demonstrates a complex and dynamic expression pattern in the developing vertebrate limb. Using degenerate PCR, we have identified a homologous gene in Xenopus and are in the process of isolating a complete cDNA clone to enable study of its role in embryonic patterning in tissue repair.

在过去的一年里，我们已经确定了五个与 骨形态发生蛋白家族的生长因子。这些蛋白质是 成为位置规范中的关键决定因素 在胚胎发育过程中的信息，并承担了重要的 生物技术社区由于其几乎肯定的治疗作用 在各种临床情况下，包括骨不连骨折和其他 矫形和重建适应症，牙槽骨隆起术， 以及其他类型的组织修复。 其中一种，抗多盐化形态发生蛋白(ADMP)，发挥了 对整个胚胎的解剖模式产生深远的影响。尽管 它在胚胎区域表达，与诱导 背部和神经结构，它深刻地抑制它们当 过度表达。到目前为止，ADMP是唯一确定的此类增长因素。 因为它的表达增加是为了响应 产生夸张的背部结构，我们认为蛋白质作用于 作为一种反馈系统，缓和自然发生的影响 体内的背部信号。 这些生长因子中不同的亚家族的两个成员，最初 在非洲爪哇基因组DNA中鉴定，然后在合作中表征 与NIDR的Frank Luyten博士有牵连 脊椎动物肢体的原位杂交发育及遗传学研究 在哺乳动物身上。这些基因被称为软骨衍生形态发生蛋白 (CDMP)仅在软骨中表达，因此是唯一生长的 已知的这种组织特有的因子。 我们还分离了哺乳动物成骨蛋白-1(OP-1)的同源物。 该基因表现出复杂和动态的表达模式(腹侧 内胚层/中胚层、眼睛、耳囊、垂体、松果体、神经轴和 鳃弓，表明在胚胎发育过程中有几个不同的作用。 该基因的过度表达导致腹侧标志物的诱导和 腹壁组织明显增殖。 BMP家族另一个新成员的部分cdna克隆已经完成。 从非洲爪哇分离出来的。该基因在原肠发育过程中表达。 胚胎的动物区域；它的生物活性仍有待于 确认身份。 最后，从牛关节分离出一种新的蛋白质的序列 软骨已经被用来分离相应的基因，这是 演示了在开发过程中复杂而动态的表达模式 脊椎动物的肢体。利用简并聚合酶链式反应，我们已经鉴定出一种同源的 基因，目前正在分离完整的cdna克隆。 以便于研究其在组织修复中胚胎构型中的作用。