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.

摘要 高血压是心血管和慢性肾脏疾病以及脑血管疾病的危险因素 功能障碍和认知能力下降。值得注意的是，在发育过程中存在性别差异。 高血压普遍克服血压控制不足和治疗抵抗 目前的高血压治疗将取决于对系统的理解，包括大脑内部， 导致男性和女性血压升高。最近有证据表明， 脑炎症因子在高血压的发生中起着关键作用。肿瘤坏死因子α (TNFα）是一种细胞因子，最初被表征为巨噬细胞衍生的信号分子，参与全身性 炎症，现在已知是在正常，可塑性和病理性神经过程中合成和释放的。 由常驻脑细胞来运作。TNFα还已知调节下丘脑网络， 交感神经和神经内分泌活动与血压。TNFα信号通过1型和2型受体 （分别为TNFR 1和TNFR 2）。TNFR 1受体是脑中主要的TNFα受体， 表达于下丘脑室旁核（PVN）。在大脑中，有证据表明TNFR 1 与谷氨酸有关键的相互作用，谷氨酸是神经信号和可塑性的重要底物， 自主调节和血压控制。值得注意的是，雌激素受体的雌激素信号转导 (ER PVN中的主要雌激素受体，参与下丘脑谷氨酸可塑性， 高血压然而，高血压时TNFR 1、ER β和谷氨酸可塑性之间的关系， 从来没有在男性和女性中建立过。该项目将测试TNFR 1 PVN神经元中的信号传导有助于与慢升压AngII相关的谷氨酸受体可塑性 以性别依赖的方式进行管理。多学科战略结合使用遗传/分子， 生物化学、神经生理学和高分辨率神经解剖学方法将用于研究 TNFR 1信号在PVN谷氨酸受体可塑性中的作用。小鼠将被制成高血压， 具有临床相关性的血管紧张素II依赖性慢发型高血压。以下具体目标 目标1.室旁核中的TNFR 1在慢升压神经元的发育中起着不同的作用 在雄性和雌性小鼠中对AngII的反应。目标二。TNFR 1差异调节PVN谷氨酸 在雄性和雌性小鼠中的受体信号。目标3。ER β参与TNFR 1的性别差异- 高血压时的谷氨酸信号这个项目有可能扩大我们对 神经炎症信号和高血压的性别差异，并提供了新的见解，神经炎症信号和高血压的性别差异， 控制血压的调节。