权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting TACE, a novel approach to the treatment of sympathetic excitation in heart failure.

靶向 TACE，一种治疗心力衰竭交感神经兴奋的新方法。

基本信息

批准号：
10306332
负责人：
Shunguang Wei
金额：
$ 38.13万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10306332
关键词：
Address Adverse effects Animals Anti-Inflammatory Agents Antiinflammatory Effect Attention Automobile Driving Binding Binding Proteins Biochemistry Biological Process Blood - brain barrier anatomy Blood Circulation Brain Brain region Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Clinical Clinical Trials Data Diabetes Mellitus Disease Disintegrins Economic Burden Electrophysiology (science)Enzymes Equilibrium Etanercept Exhibits Family Functional disorder Heart failure Hypertension Hypothalamic structure Immune response Industry Inflammation Mediators Inflammatory Inflammatory Response Injections Integral Membrane Protein Intervention Lead Light Mediating Mediator of activation protein Membrane Metabolic Diseases Metalloproteases Modeling Molecular Molecular Biology Myocardial dysfunction Neuraxis Obesity Pathogenesis Patients Peripheral Pharmacologic Substance Pharmacology Play Production Rattus Recombinants Research Project Grants Role Severities Subfornical Organ Survival Rate Systolic heart failure TNF gene TNF-alpha converting enzyme TNFRSF1A gene Techniques Testing Therapeutic Therapeutic Intervention Time Tissues Tumor Necrosis Factor Receptor Ventricular Function Work brain tissue cell type cytokine enzyme activity heart function immunocytochemistry improved infliximab insight mortality novel novel strategies novel therapeutics paraventricular nucleus protective effect receptor response

项目摘要

Heart failure (HF) is a devastating disease. Debilitation, mortality, and concomitant economic burden associated with HF all point to the need for new therapies to address this problem more effectively. Increased pro-inflammatory cytokines (PICs) in periphery and the central nervous system, particularly tumor necrosis factor-α (TNF-α), have been implicated in the pathophysiology of HF. However, anti-TNF clinical trials targeting peripheral manifestations of HF have failed to exhibit beneficial significance, indicating that the mechanisms of TNF-α have not been challenged. Our previous study discovered that TNF-α increases in cardiovascular/autonomic-related regions of the brain in a rat model of HF and contribute significantly to sympathetic excitation in that setting. More recently, our preliminary data indicated that TACE, a TNF-α converting enzyme, is upregulated in the paraventricular nucleus (PVN) of hypothalamus and subfornical organ (SFO) of the brain, and can alter cardiovascular function and sympathetic drive in HF rats. Unlike other cytokines, TNF-α is initially produced as a transmembrane protein (tmTNF-α). TACE is responsible for the cleavage of tmTNF-α to release its mature form, the soluble TNF-α (sTNF-α), to mediate inflammatory and immune responses. Further evidence indicated that sTNF-α binds predominantly to the TNF receptor 1 (TNFR1) to elicit pro-inflammatory and toxic responses and that tmTNF-α binds preferentially to the TNF receptor 2 (TNFR2) to display an anti-inflammatory and protective role. This project will underline the role of the brain TACE in TNF-α–induced inflammatory mechanisms driving the neurohumoral activation in HF. Using a multifaceted approach including electrophysiology, molecular biology, immunocytochemistry, pharmacology, and biochemistry in sham-operated and HF rats, this project will determine 1) whether TACE regulates the balance between sTNF-α and tmTNF-α in SFO and PVN in HF, and what cell types are involved; 2) whether increased TACE activity and/or decreased TNFR2 expression in brain contribute to the neurohumoral excitation in HF; 3) whether inhibition of TACE or activation of TNFR2 in the brain has a beneficial effect on cardiac function and survival rate in HF. These studies will characterize a previously unrecognized role of brain TACE in neurohumoral activation in HF and will identify a novel anti-TNF target for pharmacological intervention of HF. Completion of this research project will provide important insights into the anti-cytokine therapeutic strategy in HF and may also have implications in other cardiovascular disorders like hypertension and metabolic diseases like obesity or diabetes.

心力衰竭（HF）是一种毁灭性的疾病。虚弱、死亡和随之而来的经济负担与心力衰竭相关的所有这些都表明需要新的疗法来更有效地解决这个问题。增加外周和中枢神经系统中的促炎细胞因子（PIC），特别是肿瘤坏死 α因子（TNF-α）与心力衰竭的病理生理学有关。然而，针对 TNF 的临床试验心力衰竭的外周表现未能表现出有益的意义，这表明心力衰竭的机制 TNF-α 尚未受到挑战。我们之前的研究发现，TNF-α 会增加心力衰竭大鼠模型中大脑的心血管/自主相关区域对在那种环境下产生交感神经兴奋。最近，我们的初步数据表明 TACE，一种 TNF-α 转换酶，在下丘脑和穹窿下器官的室旁核 (PVN) 中表达上调 (SFO) 的大脑，并且可以改变心力衰竭大鼠的心血管功能和交感神经驱动。与其他不同作为细胞因子，TNF-α 最初是作为跨膜蛋白 (tmTNF-α) 产生的。 TACE 负责 tmTNF-α 裂解释放其成熟形式，即可溶性 TNF-α (sTNF-α)，从而介导炎症和免疫反应。进一步的证据表明 sTNF-α 主要与 TNF 受体 1 结合 (TNFR1) 引发促炎和毒性反应，并且 tmTNF-α 优先与 TNF 结合受体 2 (TNFR2) 发挥抗炎和保护作用。该项目将强调 TNF-α 诱导的炎症机制中大脑 TACE 驱动心衰中的神经体液激活。使用多方面的方法，包括电生理学、分子生物学、免疫细胞化学、药理学、和假手术大鼠和心力衰竭大鼠的生物化学，该项目将确定 1) TACE 是否调节 SFO 中 sTNF-α 和 tmTNF-α 以及 HF 中 PVN 之间的平衡，以及涉及哪些细胞类型； 2）是否大脑中 TACE 活性增加和/或 TNFR2 表达减少有助于神经体液高频激励； 3）抑制大脑中的TACE或激活TNFR2是否对心力衰竭患者的心功能和存活率。这些研究将描述大脑以前未被认识到的作用 TACE 在心力衰竭神经体液激活中的作用，并将确定一种新的抗 TNF 药理学靶点 HF 的干预。该研究项目的完成将为抗细胞因子提供重要的见解心力衰竭的治疗策略，也可能对高血压等其他心血管疾病有影响以及肥胖或糖尿病等代谢疾病。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Silencing Epidermal Growth Factor Receptor in Hypothalamic Paraventricular Nucleus Reduces Extracellular Signal-regulated Kinase 1 and 2 Signaling and Sympathetic Excitation in Heart Failure Rats.

DOI：
10.1016/j.neuroscience.2021.01.025
发表时间：
2021-05-21
期刊：
Neuroscience
影响因子：
3.3
作者：
Yu Y;Wei SG;Weiss RM;Felder RB
通讯作者：
Felder RB

Transforming Growth Factor-α Acts in Hypothalamic Paraventricular Nucleus to Upregulate ERK1/2 Signaling and Expression of Sympathoexcitatory Mediators in Heart Failure Rats.

DOI：
10.1016/j.neuroscience.2021.12.030
发表时间：
2022-02-10
期刊：
Neuroscience
影响因子：
3.3
作者：
Yu Y;Chen E;Weiss RM;Felder RB;Wei SG
通讯作者：
Wei SG

Stress-Induced Sensitization of Angiotensin II Hypertension Is Reversed by Blockade of Angiotensin-Converting Enzyme or Tumor Necrosis Factor-α.

压力诱导的血管紧张素 II 高血压敏化可通过阻断血管紧张素转换酶或肿瘤坏死因子-α 来逆转。

DOI：
10.1093/ajh/hpz075
发表时间：
2019
期刊：
American journal of hypertension
影响因子：
3.2
作者：
Xue,Baojian;Yu,Yang;Wei,Shun-Guang;Beltz,TerryG;Guo,Fang;Felder,RobertB;Johnson,AlanKim
通讯作者：
Johnson,AlanKim

IL (Interleukin)-17A Acts in the Brain to Drive Neuroinflammation, Sympathetic Activation, and Hypertension.