STUDY OF MICE IN WHICH THE TGF BETA 1 GENE HAS BEEN DISRUPTED

对 TGF Beta 1 基因被破坏的小鼠的研究

• 批准号: 3752781
• 负责人: A B ROBERTS
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 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/3752781
• 关键词: developmental genetics; gene mutation; genetic manipulation; growth /development; laboratory mouse; physiology; postnatal growth disorder; prenatal growth disorder; transforming growth factors

Transforming growth factor-beta (TGF-beta) has previously been implicated in embryonic development and in regulating both cell proliferation and expression of target genes. Of the three TGF-beta isoforms, type 1 TGF- beta is both the most abundant in most tissues and the most acutely regulated in injury and repair and in the pathogenesis of various diseas- es. Although they lack any obvious developmental defects, mice in which the TGF-beta1 gene has been knocked out by targeted disruption die at about 3 weeks of age of multifocal inflammatory disease. We have investigated the possible initiating event in this inflammatory syndrome and found that, prior to detection of any tissue infiltrates, expression of both class I and II major histocompatibility antigens is high in these mice, while generally undetectable in comparable tissues in normal littermates, suggesting that TGF-beta may be a natural repressor of MHC antigen expression. Moreover, we have found that the surprisingly normal development of these mice results from transfer of TGF-beta1 protein from the heterozygous mothers, both transplacentally and in the milk. By dosing with an immunosuppressant, dexamethasone, to extend the life of a female homozygous for the mutant allele, we have achieved a term delivery and been able to demonstrate that TGF-beta1 (-/-) pups born to a TGF-beta1 (-/-) mother have severe developmental defects, especially in cardiogenesis. Normal cardiogenesis is supported either by maternal transfer of TGF-beta1 from heterozygous mothers to TGF-beta1 (-/-) pups or by endogenous synthesis of TGF-beta1 in heterozygous pups born to null mothers. This demonstrates a critical role of TGF-beta1 in cardiogenesis; the role of maternal transfer of TGF-beta1 in normal physiology is not known at present.

转化生长因子-β（TGF-β）以前曾被牵连 在胚胎发育和调节细胞增殖和 目的基因的表达。 在三种TGF-β同种型中，1型TGF-β是TGF- β在大多数组织中含量最丰富， 在损伤和修复以及各种疾病的发病机制中受到调节- es. 尽管它们没有任何明显的发育缺陷， TGF-β 1基因已被靶向破坏所敲除， 约3周龄的多灶性炎性疾病。 我们有 研究了这种炎症综合征可能的起始事件 发现在检测到任何组织浸润之前， I类和II类主要组织相容性抗原在这些 小鼠，虽然在正常小鼠的可比组织中通常检测不到， 这表明TGF-β可能是MHC的天然阻遏物， 抗原表达 此外，我们还发现， 这些小鼠的发育是由于TGF-β 1蛋白从 杂合子母亲，无论是经胎盘还是在乳汁中。 通过 给药免疫抑制剂地塞米松，以延长寿命 一个突变等位基因的纯合子女性，我们已经实现了一个术语， 分娩，并能够证明TGF-β 1（-/-）幼崽出生， TGF-β 1（-/-）母亲有严重的发育缺陷， 在心脏发生中。 正常的心脏发生是由母体 TGF-β 1从杂合子母体转移到TGF-β 1（-/-）幼崽 或通过内源性合成TGF-β 1的杂合子幼崽出生的零 妈妈们 这表明TGF-β 1在 心脏发生;母亲转移TGF-β 1在正常 生理学目前还不清楚。