Hypothalamic cytokines, glutamate receptor plasticity, and blood pressure

下丘脑细胞因子、谷氨酸受体可塑性和血压

• 批准号: 9383481
• 负责人: MICHAEL J GLASS
• 金额: $ 42.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383481
• 关键词: Address; Agonist; Angiotensin II; Antihypertensive Agents; Argipressin; Biochemical; Blood Pressure; Brain; Cell membrane; Cells; Cerebrovascular Disorders; Chemosensitization; Chronic Kidney Failure; Coupled; Cytokine Signaling; Development; Disease; Essential Hypertension; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Female; Gene Expression; Glutamate Receptor; Glutamates; Gonadal Hormones; Hypertension; Hypothalamic structure; Immunoelectron Microscopy; Impaired cognition; In Situ; Inflammation; Inflammatory; Label; Light; Measures; Mediating; Modeling; Molecular Genetics; Morbidity - disease rate; Mus; Mutant Strains Mice; N-Methylaspartate; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Neurosecretory Systems; Pathologic; Phenotype; Phosphorylation; Plasticizers; Play; Population; Process; Production; Proteins; Reactive Oxygen Species; Receptor Gene; Receptor Signaling; Regulation; Reporter; Resolution; Risk Factors; Rodent; Role; Serine; Sex Characteristics; Signal Transduction; Signaling Molecule; Site; Spinal; System; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Testing; blood pressure regulation; brain cell; burden of illness; cardiovascular risk factor; cell type; clinically relevant; cytokine; gender difference; glutamatergic signaling; high resolution imaging; imaging modality; insight; knock-down; macrophage; male; mortality; multidisciplinary; neuromechanism; neurophysiology; neuroregulation; neurotransmission; novel; paraventricular nucleus; patch clamp; pre-clinical; programs; receptor; receptor expression; receptor-mediated signaling; relating to nervous system; response; sex; therapy resistant; trafficking

ABSTRACT Hypertension is a risk factor for cardiovascular and chronic kidney diseases, as well as cerebrovascular dysfunction and cognitive decline. Significantly, there are established sex differences in the development of hypertension. Overcoming the insufficiency of blood pressure control and treatment resistance commonly seen with current hypertension therapies will depend on understanding the systems, including within the brain, that are responsible for elevated blood pressure in males and females. Provocative recent evidence points to a critical role for brain inflammatory factors in the emergence of hypertension. Tumor necrosis factor alpha (TNFα) is a cytokine originally characterized as a macrophage-derived signaling molecule involved in systemic inflammation that is now known to be synthesized and released during normal, plastic, and pathological neural function by resident brain cells. TNFα is also known to modulate hypothalamic networks that coordinate sympathetic and neuroendocrine activity with blood pressure. TNFα signals via type 1 and type 2 receptors (TNFR1 and TNFR2, respectively). TNFR1 receptors are the major TNFα receptor in the brain with a high expression in the hypothalamic paraventricular nucleus (PVN). Within the brain, there is evidence that TNFR1 has key interactions with glutamate, an important substrate for neural signaling and plasticity implicated in autonomic regulation and blood pressure control. Significantly, estrogen signaling at estrogen receptor ß (ERß), the major estrogen receptor in the PVN, is involved in hypothalamic glutamate plasticity associated with hypertension. However, the relationship between TNFR1, ERß, and glutamate plasticity, during hypertension has never been established in males and females. This project will test the novel hypothesis that TNFR1 signaling in PVN neurons contributes to the glutamate receptor plasticity associated with slow-pressor AngII administration in a sex-dependent manner. A multidisciplinary strategy combining the use of genetic/molecular, biochemical, neurophysiological, and high-resolution neuroanatomical approaches will be used to investigate the role of TNFR1 signaling in glutamate receptor plasticity in the PVN. Mice will be made hypertensive by a form of angiotensin II-dependent slow onset-hypertension with clinical relevance. The following Specific Aims will be addressed: Aim 1. TNFR1 in the PVN plays differing roles in the development of the slow-pressor response to AngII in male and female mice. Aim 2. TNFR1 differentially modulates PVN glutamate receptor signaling in male and female mice. Aim 3. ERß contributes to sex-differences in TNFR1- glutamate signaling during hypertension. This project has the potential to expand our understanding of neural-inflammatory signaling and gender differences in hypertension and offer novel insights into the neural regulation of blood pressure control.

抽象的 高血压是心血管和慢性肾脏疾病的危险因素，以及脑血管 功能障碍和认知能力下降。值得注意的是，在发展方面存在性别差异 高血压。通常克服血压控制和治疗抗药性不足 当前有高血压疗法可见将取决于了解系统，包括大脑内部的系统 负责男性和女性血压升高。挑衅的最近证据表明 脑炎症因素在高血压出现中的关键作用。肿瘤坏死因子α （TNFα）是一种细胞因子，最初是巨噬细胞来源的信号分子 炎症现在已知在正常，塑料和病理中性期间已合成和释放 居民脑细胞的功能。 TNFα也已知可以调节坐标的下丘脑网络 血压的交感神经和神经内分泌活性。通过1型和2型受体的TNFα信号 （分别TNFR1和TNFR2）。 TNFR1受体是大脑中的主要TNFα受体，高 下丘脑室室核（PVN）中的表达。在大脑中，有证据表明TNFR1 与谷氨酸具有关键相互作用，谷氨酸是一种重要的基板，用于在 自主性调节和血压控制。值得注意的是，雌激素受体处的雌激素信号传导 （Erß），PVN中的主要雌激素受体，参与与下丘脑谷氨酸的可塑性有关 高血压。但是，高血压期间TNFR1，ERß和谷氨酸可塑性之间的关系 从未在男性和女性中建立过。该项目将测试TNFR1的新假设 PVN神经元中的信号传导有助于与缓慢压力的谷氨酸接收器可塑性 以性别依赖的方式给药。一种结合遗传/分子使用的多学科策略， 生化，神经生理学和高分辨率神经解剖学方法将用于研究 TNFR1信号传导在PVN中的谷氨酸受体可塑性中的作用。小鼠将通过 血管紧张素II II依赖性缓慢的催化性与临床相关性的形式。以下特定目标 将解决：PVN中的AIM1。TNFR1在慢速器的发展中扮演不同的角色 男性和雌性小鼠对Angii的反应。 AIM2。TNFR1对PVN谷氨酸的调节不同 男性和雌性小鼠的接收器信号。 AIM 3.ERß有助于TNFR1-的性别差异 - 高血压期间的谷氨酸信号传导。该项目有可能扩大我们对 神经炎症信号传导和性别差异在高血压中，并为神经元提供新的见解 调节血压控制。