Sculpting the atherosclerotic plaque by neurotrophins

通过神经营养素塑造动脉粥样硬化斑块

基本信息

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
项目类别：
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

项目摘要

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.

动脉粥样硬化的发展部分受到生长因子局部表达的调节，生长因子促进造血细胞和血管平滑肌细胞募集到新内膜中。我们之前证明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。神经营养因子在调节血管发育和调节血管对损伤的反应中的三个具体作用已被确定： (1) 神经营养蛋白介导表达 Trk B 的心脏内皮细胞的存活 (2) 神经营养蛋白诱导表达 Trk A 和 Trk B 的血管平滑肌细胞在损伤后募集到正在发育的新内膜； (3)神经营养素诱导的新内膜中表达p75NTR的平滑肌细胞的激活诱导细胞凋亡。神经营养蛋白在脉管系统中作用的悖论，介导促生存和促死亡结果，最近通过我们的鉴定得到澄清，即神经营养蛋白的前体选择性地结合促凋亡的 p75NTR，而成熟的配体选择性地激活趋化性和促进生存的 Trk 受体。我们的初步研究表明，神经营养素 NGF 和 BDNF 的前体和成熟形式在小鼠模型的人动脉粥样硬化病变和动脉粥样硬化斑块中表达，并且选择性 MMP 和纤溶酶可以将前体裂解为成熟形式。该项目的长期目标是了解神经营养素前体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态。具体目标 1 的研究将定义人类病变和动脉粥样硬化形成的小鼠模型中神经营养素的前体和成熟形式的空间和时间表达，并将它们的表达与 p75NTR 和 Trk 受体的协调表达相关联。作为 MMP 和组件纤溶酶原蛋白酶系统。具体目标 2 的研究将通过体外趋化性、存活和凋亡分析来确定前神经营养蛋白对血管平滑肌细胞、单核细胞/巨噬细胞和内皮细胞的生物作用，并将其与成熟神经营养蛋白的作用进行比较。最后，在具体目标 3 中，我们将从基因角度剖析成熟神经营养蛋白中的前神经营养蛋白在体内病变形成中的作用：用抗切割突变体替换天然 BDNF 编码外显子，仅生成前 BDNF。将评估血管损伤小鼠模型中前 BDNF 过度表达的影响。这些研究的结果可能会确定调节正在形成的动脉粥样硬化微环境的独特靶标。