Blocking Hypertension by Regulatory T-lymphocytes

通过调节性 T 淋巴细胞阻断高血压

基本信息

批准号：
8292162
负责人：
DOUGLAS F LARSON
金额：
$ 37.21万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-20 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8292162
关键词：
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Address Adoptive Transfer Advanced Glycosylation End Products Affect Angiotensin II Antihypertensive Agents Architecture Autoimmune Diseases Blood Pressure Blood Vessels CD4 Positive T Lymphocytes Cell physiology Cells Clinical Clinical Pathology Collagen Comorbidity Consensus DOCA Data Development Disease Elastin Endocrine Enzymes Equilibrium Essential Hypertension Extracellular Matrix Fibrillar Collagen Fibroblasts Functional disorder Future Goals Hypertension Immune Immune system Individual Interleukin-17 Lymphocyte Lymphocyte Function Lymphocyte Subset Mechanics Mediating Medical Modeling Molecular Molecular Target Multiple Sclerosis Mus NG-Nitroarginine Methyl Ester Neurosecretory Systems Nitric Oxide Pathogenesis Pathology Pathway interactions Play Population Prevalence Process Property Protein-Lysine 6-Oxidase Proteins Regulation Regulatory T-Lymphocyte Renal function Renin-Angiotensin System Research Rodent Model Role Smooth Muscle Sodium Stretching System Testing Therapeutic Toll-Like Receptor 2 United States Vascular remodeling arterial remodeling base cell type crosslink cytokine immunoregulation in vivo nervous system disorder novel prevent public health relevance response therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Even though neuroendocrine pathways have been systematically studied and defined as having regulatory properties of vasculature architecture related to hypertension; it has recently become evident that their effect is entirely dependent upon the CD4+ lymphocyte. Hypertension cannot be induced with angiotensin II or DOCA in CD4+ deficient mice and secondly hypertension can be adoptively transferred with CD4+ lymphocytes from hypertensive mice to naove mice. There are four subtypes of CD4+ lymphocytes; Th1, Th2, Th17, and Treg each of which have their own unique function, expressed cytokines, and effector proteins. Taken together, do the classic hypertensive neuroendocrine pathways affect balance and function of these CD4+ lymphocyte subsets? Secondly there are three major cell types in the arterial vasculature; endothelial, smooth muscle, and adventitial fibroblasts all of which are inter-connected by the vascular extracellular matrix. Therefore what is the target vascular cell and cellular function that is dependent upon by the CD4+ lymphocyte? Our over-all goal is to demonstrate that skewing of the CD4+ lymphocyte responses towards Th17 or Th1 and away from Treg by the neuroendocrine pathways may be responsible for the vascular extracellular matrix remodeling. This primary goal will focus further on select candidate Th17 and Th1 cytokines and vascular enzymes that form extracellular matrix crosslinking. We plan to compare three different rodent models of hypertension, namely; angiotensin II, DOCA, and L-NAME, with in vivo and ex vivo analysis of vascular stiffness, renal function, selected immune modulation of Th1, Th2, Th17, and Treg function, and molecular, histological, and mass spectrophotometric analysis of the concentration and composition of the vascular fibrillar collagen and elastin. The extracellular matrix compositional changes that we propose to associate with immune based hypertensive vascular stiffening is an increase in the level of lysyl oxidase mediated collagen and elastin crosslinking. In summary, we plan to demonstrate that early or pre-hypertensive states are due to a Th17/Th1 mediated alteration of the vascular extracellular matrix composition. PUBLIC HEALTH RELEVANCE: The clinical state of primary hypertension affects a large proportion of the world's population. We have therapeutics which can reduce the blood pressure but may not affect the underlying vascular pathology. Almost all anti-hypertensive therapeutics are based on modulation of the neuro-endocrine pathways. We are suggesting that the immune system and specifically their products, cytokines, regulate the composition of the vascular extracellular matrix through inducing molecular cross-links in the vascular collagen and elastin. We have shown that inhibition of one of the enzymes that form these cross-links significantly reduces vascular stiffness in vivo. More specifically, we are suggesting that Th17 cytokines induce the enzymatic formation of vascular cross-links and that regulatory T-lymphocytes inhibit this process. The future of this research will be to develop selective antagonists to our proposed immune based pathogenesis of vascular remodeling to reduce the formation of cross-links and thereby reduce vascular stiffness.

描述（由申请人提供）：即使已系统地研究并定义为具有与高血压有关的脉管结构的调节性能，即使神经内分泌途径已被系统地研究和定义；最近显而易见的是，它们的作用完全取决于CD4+淋巴细胞。在CD4+缺陷小鼠中，不能用血管紧张素II或DOCA诱导高血压，其次可以用从高血压小鼠到NAOVE小鼠的CD4+淋巴细胞来屈服于高血压。 CD4+淋巴细胞有四个亚型； Th1，Th2，Th17和Treg每个都有其独特的功能，表达的细胞因子和效应蛋白。综上所述，经典的高血压神经内分泌途径是否会影响这些CD4+淋巴细胞亚群的平衡和功能？其次，动脉脉管系统中有三种主要细胞类型。内皮，平滑肌和外在成纤维细胞所有这些都与血管外基质相互连接。因此，CD4+淋巴细胞取决于什么靶血管细胞和细胞功能？我们的全部目标是证明CD4+淋巴细胞对Th17或Th1的反应偏斜，并通过神经内分泌途径偏离Treg，可能是血管外基质重塑的原因。这个主要目标将进一步集中在形成细胞外基质交联的精选候选Th17和Th1细胞因子和血管酶。我们计划比较三种不同的高血压模型，即。血管紧张素II，DOCA和L名称，具有体内和离体分析，对血管刚度，肾功能，TH1，TH2，TH17和Treg功能的选定免疫调节，以及分子，组织学和质量分光光化的浓度和质量分光光分析，对血管纤维纤维纤维胶蛋白和Elastin and Elastin and Elastin and Elastin and Elastin and Elastin and Elastin and Elastin and Elastin。我们建议将其与免疫基高血压血管僵硬相关的细胞外基质组成变化是赖氨酸氧化酶介导的胶原蛋白和弹性蛋白交联的水平的增加。总而言之，我们计划证明早期或催眠前状态是由于Th17/Th1介导的血管外基质组成的改变。公共卫生相关性：原发性高血压的临床状态会影响世界人口的很大一部分。我们有可以降低血压但可能不会影响潜在血管病理的治疗剂。几乎所有抗高血压疗法都是基于神经内分泌途径的调节。我们建议通过诱导血管胶原蛋白和弹性蛋白中的分子交联来调节血管外基质的组成来调节血管外基质的组成。我们已经表明，抑制形成这些交联的一种酶可显着降低体内的血管僵硬。更具体地说，我们建议Th17细胞因子诱导血管交联的酶促形成，并抑制调节性T淋巴细胞抑制此过程。这项研究的未来将是为我们提出的基于免疫的血管重塑的发病机理发展选择性拮抗剂，以减少交联的形成，从而减少血管僵硬。