Modulation of Sympatho-Adrenal Function by Tissue Resident Macrophages

组织驻留巨噬细胞对交感肾上腺功能的调节

• 批准号: 10726938
• 负责人: MATTHEW WHIM
• 金额: $ 18.75万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-14 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726938
• 关键词: Acute; Adrenal Glands; Adrenal Medulla; Autonomic Dysfunction; Autonomic nervous system; Blood Glucose; Blood Pressure; Body Temperature; Catecholamines; Cause of Death; Cell secretion; Cells; Chromaffin Cells; Circulation; Diabetes Mellitus; Disease; Dysautonomias; Electrophysiology (science); Enzymes; Epinephrine; Etiology; Exposure to; Fasting; Genetic; Heart Diseases; Homeostasis; Hormones; Hypertension; Hypoglycemia; Hypotension; Immune; Immune system; Impairment; Inflammation; Insulin-Dependent Diabetes Mellitus; Macrophage; Malignant Neoplasms; Modeling; Molecular; Molecular Target; Mus; Neuroimmune; Neurons; Norepinephrine; Organ; Output; Paracrine Communication; Physiological; Population; Process; Reflex action; Respiration; Role; Signal Pathway; Signal Transduction; Site; Sympathetic Nervous System; Synapses; System; Testing; Time; Tissues; Tyrosine 3-Monooxygenase; Work; body system; cellular targeting; cholinergic; clinically significant; designer receptors exclusively activated by designer drugs; experimental study; fighting; genetic approach; immune function; in vivo; mouse model; neuropeptide Y; postsynaptic; presynaptic; prevent; response

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.

项目摘要 自主神经系统在战斗或逃跑反应期间被激活，并发挥恢复功能。 体内平衡自主神经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、呼吸率和血液 葡萄糖水平自主神经功能失调可能会产生广泛的后果， 参与I型糖尿病、高血压、癌症和许多自主神经功能障碍的病因学。因此 理解自主输出的控制对于治疗许多常见疾病状态具有意义。 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，自主神经系统和免疫系统在功能上是密切相关的。 与调节两个系统输出的双向信号通路相连。的一个方面 不太清楚的这种相互作用是这种串扰可能发生的时间尺度。 这项研究的目的是检验一个假设，即肾上腺素的释放 肾上腺交感神经元（嗜铬细胞）的信号传导受信号传导途径的调节， 涉及肾上腺髓质中的先天免疫细胞群。这个想法是非常规的，因为 肾上腺素的释放被认为是完全由神经元节前的强度控制的。 嗜铬细胞突触 为了验证这一想法，我们有两个具体的目标，我们将在小鼠中使用电生理和 化学遗传学方法在第一组实验中，我们将测试假设， 肾上腺巨噬细胞的活性足以迅速改变节前神经节的强度 通过作用于突触前位点而形成嗜铬细胞突触。我们的第二个具体目标是检验假设 肾上腺巨噬细胞参与调节嗜铬细胞分泌 肾上腺素因为可靠的肾上腺素分泌需要肾上腺素表达的增加， 酪氨酸羟化酶，我们也将确定是否巨噬细胞的化学发生刺激， 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 体内的战或逃反应，并控制肾上腺素释放到体循环中。 目前对许多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 调节交感-肾上腺活性的作用，这将大大增加细胞和 这些分子靶点可以用来治疗这些临床上重要的疾病。