Diabetic Proteome and Dysregulated Vascular Phenotype

糖尿病蛋白质组和失调的血管表型

基本信息

批准号：
7140275
负责人：
LAKSHMAN SEGAR
金额：
$ 17.88万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7140275
关键词：
biological signal transduction cell differentiation cell growth regulation cell migration clinical research diabetes mellitus diabetes mellitus genetics growth factor receptors human subject insulin receptor insulinlike growth factor intraluminal angioplasty patient oriented research phenotype postoperative complications protein biosynthesis restenosis vascular smooth muscle

项目摘要

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to better understand the diabetic regulation of vascular smooth muscle cell (VSMC) phenotype. It is clear that restenosis in diabetic patients is associated with exaggerated VSMC growth. The specific objective is to determine the in vitro effects of diabetic restenotic patients' sera, and the in vivo effects of diabetes on VSMC differentiation protein(s) expression, and migratory/proliferative signals. Recent studies have shown that atherectomy specimens from angioplasty patients, injured human saphenous vein, and streptozotocin-diabetic rat VSMC exhibit decreased expression of differentiation proteins, including SM alpha-actin, or smoothelin, leading to increased VSMC growth. Neointimal growth is associated with VSMC activation of key growth signals [extracellular signal-regulated kinases, ERK1/2; focal adhesion kinase, FAK; PI3K/Akt; and mammalian target of rapamycin, mTOR]. Rapamycin (mTOR inhibitor) inhibition of VSMC growth increases contractile phenotype. Preliminary studies reveal that restenotic patients' sera stimulate VSMC proliferation to a greater extent than PDGF. Transfection of VSMC with target-specific siRNA(s) down-regulates specific growth/insulin signaling. Together, these findings lead to the hypothesis that diabetic accentuation of VSMC dedifferentiation leads to exaggerated VSMC growth in the arterial wall. Specific Aim 1 will determine the effects of restenotic patients' sera (diabetic vs nondiabetic) on VSMC differentiation protein expression, and migratory/proliferative signaling. Specific Aim 2 will examine the diabetic regulation of human arterial phenotype and the associated alterations in the balance between arterial/VSMC differentiation protein(s) expression and key growth signaling. These studies will investigate the integrated roles of key 'growth signal transducing/differentiation proteins (proteome)' toward diabetic regulation of VSMC phenotype, and will provide novel approaches for rational therapeutic targeting to prevent enhanced restenosis/coronary grafting failure in diabetic patients.

描述（由申请人提供）：拟议研究的总体目标是更好地了解血管平滑肌细胞（VSMC）表型的糖尿病调节。显然，糖尿病患者的再狭窄与夸张的VSMC生长有关。具体目标是确定糖尿病再狭窄患者血清的体外作用，以及糖尿病对VSMC分化蛋白表达的体内影响以及迁移/增殖信号。最近的研究表明，来自血管成形术患者的动脉切除术标本，损伤的人隐静脉损伤和链蛋白酶糖尿病 - 糖尿病大鼠VSMC伴有分化蛋白的表达降低，包括SMα-肌动蛋白或光滑蛋白，导致VSMC生长增加。新的生长与关键生长信号的VSMC激活有关[细胞外信号调节激酶，ERK1/2；局灶性粘附激酶，FAK； pi3k/akt;和雷帕霉素的哺乳动物靶标，mtor]。雷帕霉素（MTOR抑制剂）对VSMC生长的抑制作用增加了收缩表型。初步研究表明，再静脉曲张患者的血清比PDGF更大程度地刺激VSMC增殖。用目标特异性siRNA转染VSMC会下调特定的生长/胰岛素信号传导。总之，这些发现导致了以下假设：VSMC去分化的糖尿病强调会导致动脉壁中夸张的VSMC生长。具体的目标1将确定再替氏病患者的血清（糖尿病与非糖尿病患者）对VSMC分化蛋白表达以及迁移/增殖信号的影响。具体目标2将检查人动脉表型的糖尿病调节以及动脉/VSMC分化蛋白表达和关键生长信号传导之间平衡的相关改变。这些研究将研究关键的“生长信号转导/分化蛋白（蛋白质组）”对VSMC表型的糖尿病调节的综合作用，并将为糖尿病患者的理性治疗靶向提供新颖的方法，以防止增强糖尿病患者的再生毒/冠状动脉疗法衰竭。