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， 高脂血症 同样，再狭窄是过度的血管病变， 对球囊扩张术引起的急性损伤的反应，或 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。但会变成慢性病， 狭窄性纤维增生性疾病 因此，一个至关重要的问题是： 哪些因素区分正常血管修复和 纤维增生性血管疾病 我们的研究集中在 转化生长因子-β（TGF-β 1），因为它是由 它可以调节动脉粥样硬化形成的关键步骤 和再狭窄：细胞迁移、增殖、细胞外基质 合成、钙化和细胞凋亡。 在人类和动物中 模型，我们已经确定，平滑肌细胞（SMC） 来源于血管病变的抗增殖药物 TGF-β 1的作用，有效抑制正常SMC。 然而，TGF-β 1诱导基质积累的能力 仍然完好无损。 这种对TGF-β 1的异常反应与 选择性降低II型受体的表达， TGF-β 1及其mRNA的稳态水平较低。 将正常II型受体cDNA转染至病变来源的 SMC恢复对TGF-β 1的抗增殖反应。 的 II型受体具有2个微卫星重复序列，使其易于 复制错误会破坏基因或导致 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细胞中， 人动脉粥样硬化组织和从它们生长的细胞中。 的 拟议中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，并在人类冠状动脉 活组织检查 基因重排突变的存在， 然后II型受体将与以下疾病的进展相关： 人类和实验动物的疾病。的因果 这些突变与血管疾病的关系将通过 使用基因治疗方法引入突变受体，以及 相反，抗突变受体，进入动物和血管 细胞和血管损伤的动物模型。 的影响 体外对TGF-β 1反应的遗传操作，以及 体内血管损伤的进展将被定量。 的 结果将研究获得性TGF-β 1的全新作用， 在非肿瘤性血管疾病中， 相关性和机制水平。

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.