Sculpting the atherosclerotic plaque by neurotrophins

通过神经营养素塑造动脉粥样硬化斑块

• 批准号: 7406109
• 负责人: BARBARA L HEMPSTEAD
• 金额: $ 42.43万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7406109
• 关键词: Animals; Apolipoprotein E; Apoptosis; Apoptotic; Arterial Fatty Streak; Binding; Biological; Blood Vessels; Brain-Derived Neurotrophic Factor; Cardiac; Cell Death; Cells; Cessation of life; Chemotaxis; Class; Cleaved cell; Code; Development; Endopeptidases; Endothelial Cells; Exons; Family; Goals; Growth Factor; Hematopoietic; Human; In Vitro; Injury; Lesion; Ligands; Localized; Matrix Metalloproteinases; Mediating; Modeling; Mus; NGFR Protein; Nerve Growth Factor 1; Nerve Growth Factor Pathway; Neurons; Neurotrophin 3; Outcome; Peptide Hydrolases; Plasmin; Plasminogen; Protein Overexpression; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Resistance; Role; Site; Smooth Muscle Myocytes; System; Techniques; Tumor Necrosis Factor Receptor; Vascular remodeling; brain-derived neurotrophic factor precursor; femoral artery; gene replacement; in vivo; macrophage; member; monocyte; mutant; neurotrophic factor; receptor; response to injury; transcriptional coactivator p75

The development of atheroma is regulated in part by the localized expression of growth factors that promote the recruitment of hematopoietic cells as well as vascular smooth muscle cells into the neointima. We previously demonstrated that the neurotrophins and their receptors, the trk family of receptor tyrosine kinases and the p75 neurotrophin receptor (p75NTR), are highly expressed in atherosclerotic lesions. Three specific roles for the neurotrophins in regulating vessel development and in modulating the vascular response to injury have been identified: (1) neurotrophin-mediates survival of Trk B-expressing cardiac endothelial cells (2) neurotrophin-induced recruitment of Trk A and Trk B-expressing vascular smooth muscle cells to the developing neointima following injury; (3) neurotrophin-induced activation of p75NTR-expressing smooth muscle cells in the neointima induces apoptotic cell death. The paradox of neurotrophin actions in the vasculature, mediating both pro-survival and pro-death outcomes, has recently been clarified by our identification that the pro-forms of the neurotrophins selectively bind to the proapoptotic p75NTR, whereas the mature ligand selectively activates the chemotactic and survival promoting Trk receptors. Our preliminary studies indicate that both the pro- and mature forms of the neurotrophins NGF and BDNF are expressed in human atherosclerotic lesions and atheroma from murine models, and that selective MMPs and plasmin can cleave pro-forms to mature forms. The long term goals of this project are to understand how the differential expression of pro- and mature forms of neurotrophins regulate the dynamics of lesion formation and vascular remodeling. Studies in Specific Aim 1 will define the spatial and temporal expression of the pro- and mature forms of the neurotrophins in human lesions and in murine models of atheromata formation and correlate their expression with the co-ordinate expression of p75NTR and Trk receptors, as well as MMPs and components of the plasminogen protease system. Studies in Specific Aim 2 will identify the biological actions of the pro-neurotrophins on vascular smooth muscle cells, monocytes/macrophages and endothelial cells using in vitro analysis of chemotaxis, survival and apoptosis and compare them to the actions of the mature neurotrophins. Finally, in Specific Aim 3, we will genetically dissect the actions of the pro-neurotrophins from mature neurotrophins in lesion formation in vivo by replacing the native BDNF coding exon with a cleavage resistant mutant to generate only pro-BDNF. The effects of pro-BDNF overexpression in murine models of vascular injury will be assessed. The results of these studies may identify unique targets to regulate the microenvironment of the developing atheroma.

动脉瘤的发展部分受生长因子的局部表达，从而促进造血细胞以及血管平滑肌细胞募集到新内膜中。我们先前证明了神经营养蛋白及其受体，受体酪氨酸激酶的TRK家族和p75神经营养蛋白受体（P75NTR）在动脉粥样硬化病变中高度表达。已经确定了神经营养蛋白在调节血管发育和调节损伤的血管反应方面的三个特定作用： （1）神经营养蛋白 - 表达TRK的心脏内皮细胞的存活（2）神经营养蛋白诱导的TRK A和TRK B表达血管平滑肌细胞的募集到受伤后发育中的Neininma； （3）神经营养蛋白诱导的p75ntr表达平滑肌细胞的激活会诱导凋亡细胞死亡。我们的鉴定，神经营养蛋白作用在脉管系统中的悖论，介导了促卵巢和促进灭绝结果，我们的鉴定已经阐明了神经营养蛋白的亲蛋白的亲形式选择性地与促凋亡的p75NTR结合，而成熟的Ligand则选择性地激活了化学促进的促进和生存的特性。我们的初步研究表明，神经营养蛋白NGF和BDNF的促和成熟形式在鼠模型的人动脉粥样硬化病变和动脉粥样硬化中都表达 纤溶酶可以将促形式切割至成熟形式。该项目的长期目标是了解神经营养蛋白的促和成熟形式的差异表达如何调节病变形成和血管重塑的动力学。特定目标1中的研究将定义人病变中神经营养蛋白促和成熟形式的空间和时间表达，以及在大动脉瘤形成的鼠模型中，并将其表达与P75NTR和TRK受体的坐标表达以及MMP和MMP的坐标表达相关。 纤溶酶原蛋白酶系统。特定目标2中的研究将使用趋化性，生存和凋亡的体外分析，将促神蛋白在血管平滑肌细胞，单核细胞/巨噬细胞和内皮细胞上的生物学作用进行比较，并将其与成熟神经营养蛋白的作用进行比较。最后，在特定的目标3中，我们将通过基因剖析促神经营养蛋白的作用，从成熟的神经营养蛋白在体内的病变形成中，由成熟的神经营养蛋白通过 用抗裂解的突变​​体代替天然BDNF编码外显子，以仅产生pro-bDNF。将评估前BDNF过表达在血管损伤的鼠模型中的影响。这些研究的结果可能会确定独特的靶标，以调节发展中的动脉瘤的微环境。