Hypothalamic cytokines, glutamate receptor plasticity, and blood pressure

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，在发育过程中存在着明显的性别差异 高血压。共同克服血压控制不足和治疗阻力 目前的高血压疗法将取决于对系统的了解，包括大脑内的系统， 导致男性和女性血压升高的基因。最近具有挑衅性的证据表明 脑炎性因子在高血压发病中的关键作用。肿瘤坏死因子-α 肿瘤坏死因子α是一种细胞因子，最初是一种巨噬细胞衍生的信号分子，参与系统性红斑狼疮 现在已知在正常、可塑性和病理性神经中合成和释放的炎症 由常驻脑细胞发挥作用。众所周知，肿瘤坏死因子α还可以调节下丘脑网络的协调 交感神经和神经内分泌活动与血压。肿瘤坏死因子α通过1型和2型受体传递信号 (分别为TNFR1和TNFR2)。肿瘤坏死因子受体1受体是脑内主要的肿瘤坏死因子α受体，具有较高的 在下丘脑室旁核(PVN)表达。在大脑内，有证据表明TNFR1 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，与 自主调节和血压控制。值得注意的是，雌激素受体上的雌激素信号 下丘脑谷氨酸可塑性与下丘脑谷氨酸可塑性有关。 高血压。然而，在高血压期间，TNFR1、ER？和谷氨酸可塑性之间的关系 从未在男性和女性身上得到证实。该项目将检验新的假设，即TNFR1 下丘脑室旁核神经元中的信号参与慢升压性血管紧张素Ⅱ相关的谷氨酸受体可塑性 以性别依赖的方式进行管理。一种结合使用遗传/分子的多学科策略， 将使用生化、神经生理学和高分辨率神经解剖学方法来研究 TNFR1信号在PVN谷氨酸受体可塑性中的作用小鼠将通过一种药物引起高血压 血管紧张素II依赖型缓发性高血压与临床的相关性。以下是具体目标 将解决：目标1.室旁核中的TNFR1在慢升压的发育过程中扮演不同的角色 雄性和雌性小鼠对血管紧张素转换酶的反应。目的2.TNFR1对PVN谷氨酸的差异性调节作用 雄性和雌性小鼠的受体信号。目标3.ER？有助于TNFR1的性别差异-- 高血压时的谷氨酸信号转导。这个项目有可能扩大我们对 高血压患者的神经炎症信号和性别差异以及对神经的新认识 调节血压控制。

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.