CLINICAL AND MOLECULAR ANALYSIS OF VASCULAR TGF BETA

动脉粥样硬化似乎反映了血管对慢性 血管损伤，如高血压、吸烟和 高脂血症。同样，再狭窄是一种过度的血管 对气囊成形术引起的急性损伤的反应 粥样斑块切除术。然而，在大多数情况下，动脉粥样硬化和 再狭窄病变是可逆的。但可以转化为慢性的， 狭窄，纤维增生性疾病。因此，一个至关重要的问题是： 哪些因素将正常的血管修复与 纤维增生性血管疾病？我们的研究主要集中在 转化生长因子-β(TGF-β1)，因为它是由 通过血管细胞调节动脉粥样硬化形成中的关键步骤 与再狭窄：细胞迁移、增殖、细胞外基质 合成、钙化和细胞凋亡。对人类和动物都是如此 模型，我们已经确定了平滑肌细胞(SMC) 来自血管病变的对抗增殖剂具有抵抗力 有效抑制正常SMC的转化生长因子-β1的作用。 然而，转化生长因子-β1诱导基质堆积的能力 仍然完好无损。这种对转化生长因子-β1的异常反应与 选择性降低血管紧张素Ⅱ受体的表达 转化生长因子-β1及其mRNA的稳态表达水平降低。 正常II型受体基因在病变组织中的表达 SMC可恢复对转化生长因子-β1的抗增殖反应。这个 II型受体有两个微卫星重复，使其易于 到复制错误，使基因失活或导致 一个功能失调的受体的表达。我们的初步数据 表明这些区域的突变发生在填充的细胞 人类动脉粥样硬化组织及其生长的细胞。这个 拟议的研究将在动物模型中诊断这些突变 再狭窄和动脉粥样硬化的风险，以及人类冠状动脉 活组织检查。基因重排突变在慢性粒细胞白血病中的存在 然后，II型受体将与血管病变的进展相关 人类和实验动物中的疾病。因果关系 这些突变与血管疾病的关系将通过以下方式进行测试 使用基因治疗方法引入突变受体，以及 相反，耐突变受体，进入动物和血管 细胞，并进入血管损伤的动物模型。美国政府的影响 遗传操作对转化生长因子-β1体外反应的影响 血管损伤在体内的研究进展，将被量化。这个 结果将调查获得性转化生长因子-β1的全新作用 两组非肿瘤性血管疾病患者的受体突变 关联性和机械性层面。

Atherosclerosis appears to reflect a vascular response to chronic vascular injuries such as hypertension, smoking, and hyperlipidemia. Likewise, restenosis is an excessive vascular response to acute injury induced by balloon agnioplasty or atherectomy. In most cases however, both atherosclerotic and restenotic lesions are reversible. But can convert to chronic, stenosing, fibroproliferative disease. Thus, a vital question is: What factors distinguish normal vascular repair from fibroproliferative vascular disease? Our studies have focused on transforming growth factor-beta (TGF-beta1) because it is produced by vascular cells and it can modulate the key steps in atherogenesis and restenosis: cell migration, proliferation, extracellular matrix synthesis, calcification, and apoptosis. In both humans and animal models, we have determined that smooth-muscle cells (SMC) derived from vascular lesions are resistant to the antiproliferative effect of TGF-beta1, which potently inhibits normal SMC. However, the ability of TGF-beta1 to induce matrix accumulation remains intact. This aberrant response to TGF-beta1 is related to a selective decrease in the expression of the Type II receptor for TGF-beta1 and lower steady-state levels of its mRNA. Transfection of a normal Type II receptor cDNA into lesion-derived SMC restores the antiproliferative response to TGF-beta1. The Type II receptor possesses 2 microsatellite repeats, making it prone to replication errors which inactivate the gene or cause the expression of a dysfunctional receptor. Our Preliminary Data indicates that mutations in these regions occur in cells populating human atherosclerotic tissues and in cells grown from them. The proposed studies would diagnose these mutations in animal models of restenosis and atherosclerosis, and in human coronary artery biopsies. The presence of mutations of gene rearrangements in the Type II receptor will then be correlated with the progression of disease in humans and experimental animals. The causal relationship of these mutations to vascular disease will be tested by using a gene therapy approach to introduce mutant receptors, and conversely, mutation-resistant receptors, into animal and vascular cells, and into animal models of vascular injury. The effect of the genetic manipulations on the response TGF-beta1 in vitro, and on the progress of vascular lesion in vivo, will be quantitated. The results will investigate an entirely new role for acquired TGF-beta1 receptor mutations in non-neoplastic vascular disease on both a correlational and mechanistic level.