Brain-Gut Microbiome-Immune Axis in Hypertension

高血压中的脑肠微生物组免疫轴

• 批准号: 9122989
• 负责人: Carl J Pepine
• 金额: $ 61.79万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122989
• 关键词: Acetates; Address; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Antihypertensive Agents; Attenuated; Autonomic nervous system; Bone Marrow; Brain; Brain region; Butyrates; Cardiovascular Diseases; Cells; Chronic Kidney Failure; Clinical; Communication; Data; Development; Diabetes Mellitus; Disease; Drug resistance; Equilibrium; Event; Exhibits; Failure; Functional disorder; Genomics; Hematopoietic stem cells; Human; Hypertension; Hypotension; Immune; Inbred SHR Rats; Inflammation; Infusion procedures; Intestines; Life Style; Link; Mediating; Microbe; Microglia; Minocycline; Modeling; Motion; Mus; Myelogenous; Myeloid Progenitor Cells; Nerve; Neurons; Obesity; Obstructive Sleep Apnea; Outcome; Outcome Study; Patients; Peripheral; Permeability; Pharmacotherapy; Physiological; Pilot Projects; Plasma; Population; Predisposition; Process; Production; Publishing; Rattus; Reactive Oxygen Species; Research Personnel; Resistance; Resistant Hypertension; Risk Factors; Rodent; Signal Transduction; Sympathectomy; Techniques; Therapeutic; Volatile Fatty Acids; base; blood pressure reduction; brain dysfunction; cardiovascular disorder risk; chemokine; cytokine; genetic risk factor; gut microbiome; gut microbiota; innovation; metabolic profile; microbial; modifiable risk; neuroinflammation; novel; novel strategies; paraventricular nucleus; progenitor; public health relevance; renal artery; therapeutic development; translational study

 DESCRIPTION (provided by applicant): Hypertension (HTN) is the most prevalent modifiable risk for cardiovascular disease (CVD) and disorders directly influencing CVD (i.e. diabetes, chronic kidney disease, obstructive sleep apnea, etc.). Despite lifestyle changes and advances in drug therapy, ~20% of all HTN patients are resistant to (or require ≥3) antihypertensive drugs Resistant HTN (R-HTN) is generally neurogenic in origin and associated with a dysfunctional autonomic nervous system. Few treatment options remain available following the recent failure of percutaneous renal artery sympathetic denervation (SYMPLICITY HTN-3, PRAUGE-15). Thus, a mechanism- based breakthrough is imperative to develop novel strategies to control and potentially cure R-HTN. We believe that our evidence of gut dysbiosis and dysfunctional brain-gut-bone marrow (BM) interaction in R-HTN represents this breakthrough. We propose a brain-gut-BM dysfunctional interaction hypothesis: HTN risk factors increase sympathetic drive by influencing autonomic brain regions, setting in motion a sequence of critical signaling events key to establishing neurogenic R-HTN. This includes increased gut stiffness, permeability and inflammation leading to gut microbial dysbiosis. Dysbiosis-associated changes increase BM production of myeloid progenitors and other proinflammatory cells. This contributes to increased peripheral inflammation, and neuroinflammation, as some BM-derived myeloid progenitors migrate to the paraventricular nucleus (PVN), and differentiate into microglia. Therefore, we hypothesize that establishment of R-HTN is caused by an increased SNA-mediated gut dysbiosis, activity of BM proinflammatory cells, and neuroinflammation. Three specific aims are proposed to support/refute this dysfunctional brain-gut-BM linked neuroinflammation hypothesis in R-HTN: Aim 1 will investigate the hypothesis that increased gut SNA is critical in enhanced intestinal permeability, proinflammatory conditions, and microbial dysbiosis in HTN. Aim 2 will define how gut dysbiosis increases production of proinflammatory progenitors and neuroinflammation in HTN. Aim 3 will evaluate the hypothesis that human R-HTN is linked to profound gut microbial dysbiosis and that treatment with minocycline will reverse the dysbiosis and lower BP. These studies will utilize state-of-the-art integrative physiological genomic techniques and will be conducted by an exceptional team of investigators. Thus, the outcome of this mechanism-based translational study spanning from mice to humans will provide the basis for development of paradigm-changing therapeutic approaches for R-HTN without involving more anti-hypertensive drugs.

 描述（由适用提供）：高血压（HTN）是心血管疾病（CVD）最普遍的风险，并且疾病直接影响CVD（即糖尿病，慢性肾脏疾病，阻塞性睡眠呼吸暂停等）。尽管生活方式的改变和药物治疗的进展，但所有HTN患者中约有20％耐药（或需要≥3）抗高血压药物抗性HTN（R-HTN）的起源通常是神经源性的，并且与功能障碍的自主神经神经系统有关。在最近的经皮肾动脉交感神经去神经（Symplicity HTN-3，Prauge-15）失败之后，几乎没有治疗方案可用。这是基于机制的突破，必须制定新的策略来控制和治愈R-HTN。我们认为，R-HTN中肠道营养不良和功能障碍的脑肠骨骨髓（BM）相互作用的证据代表了这一突破。我们提出了一个脑态-BM功能障碍的相互作用假设：HTN风险因素会通过影响自主的大脑区域增加交感神经驱动，从而使一系列临界信号事件序列，这是建立神经源性R-HTN的关键。这包括增加肠道刚度，渗透性和炎症导致肠道微生物营养不良。与营养不良相关的变化增加了髓样祖细胞和其他促炎细胞的BM产生。这有助于增加周围感染和神经炎症性，因为一些BM衍生的髓样祖细胞迁移到室室核（PVN）并分化为小胶质细胞。因此，我们假设建立R-HTN是由SNA介导的肠癌，BM促炎细胞的活性和神经炎症引起的。提出了三个具体目的，以支持/反驳R-HTN：AIM 1中的这种功能失调的脑gM神经炎症假说：AIM 1将调查肠内增加的肠道SNA对于增强的肠道通透性，促脑膜炎疾病和HTN中的微生物营养不良至关重要。 AIM 2将定义肠道营养不良如何增加HTN中促炎祖细胞和神经炎症的产生。 AIM 3将评估人类R-HTN与深层肠道微生物营养不良有关的假设，而用米诺环素治疗将逆转营养不良和较低的BP。这些研究将利用最先进的综合物理基因组技术，并将由一个杰出的研究者团队进行。这是从小鼠到人类的这种基于机制的转化研究的结果，将为R-HTN改变范式改变范式的治疗方法提供基础，而无需涉及更多抗高血压药物。