Modulation of Sympatho-Adrenal Function by Tissue Resident Macrophages

项目总结 自主神经系统在战斗或逃跑反应过程中被激活，并恢复功能 动态平衡。自主活动可以改变每个主要器官系统的功能，并调节每个 重要的生理变量包括血压、体温、呼吸频率和血液 血糖水平。自主神经功能失调可能会产生广泛的后果，并且是 参与I型糖尿病、高血压、癌症和许多自主性障碍的病因学研究。因此， 了解自主神经输出的控制对治疗许多常见疾病状态具有重要意义。 大多数研究强调中枢神经系统和下行活动在决定自主神经功能中的作用。 然而，最近的研究表明，自主神经和免疫系统在功能上是紧密联系的 与调节两个系统输出的双向信号通路相连。从一个方面来说 这种相互作用还没有被很好地理解，这就是这种串扰可以发生的时间尺度。 这项拟议的研究的目的是检验这样一种假设，即肾上腺素的释放 来自肾上腺的交感神经元(嗜铬细胞)受一条信号通路的调节，该信号通路 涉及肾上腺髓质中的一群先天免疫细胞。这个想法是非传统的，因为 肾上腺素的释放被认为完全由神经节前→的强度控制 嗜铬细胞突触。 为了测试这一想法，我们有两个具体的目标，我们将在小鼠身上使用电生理和 化学发生学方法。在第一组实验中，我们将测试以下假设 肾上腺巨噬细胞的活性足以迅速改变节前→的强度 嗜铬细胞通过作用于突触前轨迹进行突触。我们的第二个具体目标是检验这一假设 肾上腺巨噬细胞参与调节嗜铬细胞的分泌能力 肾上腺素。因为可靠的肾上腺素分泌需要增加肾上腺皮质激素的表达 酪氨酸羟化酶，我们还将确定巨噬细胞的化学生成刺激是否 足以提高这种酶的水平。最后，我们将测试巨噬细胞是否参与了 体内的战斗或逃跑反应，并控制肾上腺素的释放进入体循环。 目前对多种形式的自主神经功能障碍的治疗是有限的。如果肾上腺巨噬细胞发挥作用 在调节交感-肾上腺活动中的作用这将大大扩大细胞和 可以用来治疗这些临床上重要疾病的分子靶点。

PROJECT SUMMARY The autonomic nervous system is activated during the fight-or-flight response and functions to restore homeostasis. Autonomic activity can alter the function of every major organ system and regulates every significant physiological variable including blood pressure, body temperature, respiration rate and blood glucose levels. Dysregulation of autonomic function can have widespread consequences and is causally involved in the etiology of type I diabetes, hypertension, cancer and many dysautonomias. Thus understanding the control of autonomic output has implications for treating many common disease states. Most studies emphasize the role of the CNS and descending activity in determining autonomic function. However, recent work has shown that the autonomic and immune systems are functionally closely connected with bidirectional signaling pathways that regulate the output of both systems. One aspect of this interaction that is not well understood is the time scale over which this crosstalk can take place. The objective of the proposed study is to test the hypothesis that the release of the hormone epinephrine from sympathetic neurons (chromaffin cells) in the adrenal gland is regulated by a signaling pathway that involves a population of innate immune cells in the adrenal medulla. This idea is unconventional because epinephrine release is thought to be exclusively controlled by the strength of the neuronal preganglionic → chromaffin cell synapse. To test this idea we have two specific aims that we will address in mice using electrophysiological and chemogenetic approaches. In the first set of experiments we will test the hypothesis that changing the activity of adrenal macrophages is sufficient to rapidly change the strength of the preganglionic → chromaffin cell synapse by acting at a presynaptic locus. Our second specific aim is to test the hypothesis that adrenal macrophages are involved in regulating the ability of the chromaffin cells to secrete epinephrine. Because reliable epinephrine secretion requires an increase in the adrenal expression of tyrosine hydroxylase, we will also determine whether the chemogenetic stimulation of macrophages is sufficient to elevate the levels of this enzyme. Finally, we will test whether macrophages are involved in the fight-or-flight response in vivo and control the release of epinephrine into the systemic circulation. The current treatments for many forms of autonomic dysfunction are limited. If adrenal macrophages play a role in regulating sympatho-adrenal activity this would substantially widen the number of cellular and molecular targets that could be exploited to treat these clinically significant disorders.