Chronic Widespread Pain in HIV: Novel Mechanisms and Therapeutics

HIV 引起的慢性广泛疼痛：新机制和治疗方法

基本信息

批准号：
10619643
负责人：
Saurabh Aggarwal
金额：
$ 37.13万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10619643
关键词：
Absence of pain sensation Acquired Immunodeficiency Syndrome Address Advisory Committees Analgesics Antioxidants Apoptosis Attenuated Awareness Behavior Binding Blood Blood specimen Bromides CD4 Lymphocyte Count Cells Chronic Disease Clinical Coupled Disease Dynorphin A Endoplasmic Reticulum Failure Genetic HIV HIV Infections HIV Seronegativity HIV-1 Heme Hemolysis Hemopexin Homeostasis Hyperalgesia Hypersensitivity Impairment Individual Infection Inflammatory Injections International Knowledge Leukocytes Life Expectancy Link Lymphocyte Macrophage Measures Mediating Methionine Enkephalin Modeling Mus Musculoskeletal Pain Nature Neurons Neuropathy Nociception Opioid Opioid Antagonist Opioid Peptide Opioid Receptor Overdose Pain Pathogenesis Patient Self-Report Patients Peptide Synthesis Peripheral Persons Phenotype Plasma Predisposition Prevalence Proteins Quality of life Rat Transgene Rattus Research Resolution Role Sensory Source TLR4 gene Testing Therapeutic Therapeutic Intervention Viral Load result Work addiction antiretroviral therapy behavior measurement beta-Endorphin chronic inflammatory disease chronic pain chronic widespread pain comorbidity cytokine disability endogenous opioids endoplasmic reticulum stress experimental study functional disability heme a improved inhibitor innovation monocyte neuroAIDS neutrophil non-opioid analgesic novel pain sensitivity pharmacologic potential biomarker pre-clinical prevent therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT The advent and access to new treatments have made infection with human immunodeficiency virus (HIV) a chronic disease, allowing patients to have a nearly normal life expectancy. However, the prevalence of chronic widespread pain (CWP) in individuals infected with HIV is high, ranging from 25% to 85%, despite low viral load and adequate CD4 count. CWP is one of the most common associated comorbidities of HIV infection and is associated with high rate of disability and decreased quality of life. However, the specific mechanisms that contribute to CWP in HIV are not understood. Thus, pharmacological and non-pharmacological approaches to mitigate CWP have had minimal benefits, contributing to an overreliance on opioids and alarming rise in addiction and overdose. The overall objective of this proposal is to address the gap in the knowledge of the pathogenesis of CWP and identify potential biomarkers and therapeutic targets to mitigate CWP in HIV. Specifically, we will explore the role of cell-free heme in impairment of endogenous opioid synthesis/release from peripheral leukocytes in HIV patients with CWP. Our novel preliminary findings demonstrate that HIV patients who self- report having CWP have elevated plasma levels of cell-free heme, coupled with decreased leukocyte β- endorphin levels, relative to HIV patients without CWP. Heme is a pro-inflammatory molecule that can induce endoplasmic reticulum stress, as well as inhibit function of leukocytes. Heme also promotes the transition of M0 macrophages toward an M1-like pro-inflammatory rather than M2-like proresolution phenotype. Compared to M2 cells, M1 macrophages contain and release lower amounts of opioid peptides. Therefore, we hypothesize that cell-free heme reduces endogenous opioid peptide-dependent analgesia and enhances pain sensitivity in PWH. We will accomplish our overall objective by addressing the following specific aims: 1) establish a direct link between plasma concentration of cell-free heme and peripheral endogenous opioid peptides with quantitative sensory measures in HIV patients with CWP, 2) to determine in a translational manner the mechanisms through which heme contributes to diminished peripheral opioid release and pain, and 3) test whether heme scavenging is a therapeutic option to increase leukocyte endogenous opioids and attenuate pain hypersensitivity. This work is novel as the impact of endogenous opioid peptide synthesis and release by leukocytes on CWP in HIV has never before been directly examined. Furthermore, the proposed work is innovative in that it combines clinical and preclinical experiments, including the use of the HIV-1 transgenic rat model, to identify potential biomarkers and mechanisms of CWP in HIV. The proposed research is significant because, if our hypotheses are confirmed, we will identify: 1) heme as a major driver of pain in HIV, and 2) heme scavenging by hemopexin as a novel, non-opioid therapeutic for HIV-associated pain.

项目概要/摘要新疗法的出现和获得使得人类免疫缺陷病毒 (HIV) 感染成为一种常见的疾病。慢性病，使得患者拥有接近正常的预期寿命，然而慢性病的患病率却很高。尽管病毒载量较低，但 HIV 感染者的广泛性疼痛 (CWP) 较高，范围为 25% 至 85% 和足够的 CD4 计数是 HIV 感染最常见的相关合并症之一。然而，具体机制却与高残疾率和生活质量下降有关。因此，药物和非药物方法对 HIV 中 CWP 的影响尚不清楚。缓解 CWP 的好处微乎其微，导致对阿片类药物的过度依赖和成瘾率的惊人上升该提案的总体目标是解决发病机制知识方面的空白。的 CWP 并确定潜在的生物标志物和治疗靶点，以减轻 HIV 的 CWP。探索无细胞血红素在外周内源性阿片类药物合成/释放受损中的作用我们新的初步研究结果表明，患有 CWP 的 HIV 患者的白细胞。报告称，CWP 的血浆无细胞血红素水平升高，同时白细胞 β- 降低与没有 CWP 的 HIV 患者相比，血红素是一种促炎分子，可诱导内啡肽水平。内质网应激以及抑制白细胞功能也促进M0的转变。与 M2 相比，巨噬细胞倾向于 M1 样促炎表型，而不是 M2 样促消退表型。细胞中，M1 巨噬细胞含有并释放少量的阿片肽。无细胞血红素可减少内源性阿片肽依赖性镇痛并增强 PWH 的疼痛敏感性。我们将通过解决以下具体目标来实现我们的总体目标：1）建立直接链接无细胞血红素和外周内源性阿片肽血浆浓度之间的定量分析患有 CWP 的 HIV 患者的感觉测量，2) 以转化方式确定通过哪种血红素有助于减少外周阿片类药物释放和疼痛，以及 3) 测试血红素是否清除是一种增加白细胞内源性阿片类药物并减轻疼痛过敏的治疗选择。是新颖的，因为内源性阿片肽合成和白细胞释放对 HIV 中 CWP 的影响此外，拟议的工作具有创新性，因为它结合了临床。和临床前实验，包括使用 HIV-1 转基因大鼠模型，以确定潜在的生物标志物以及 CWP 在 HIV 中的作用机制拟议的研究意义重大，因为如果我们的假设得到证实，我们将确定：1) 血红素是艾滋病毒疼痛的主要驱动因素，2) 血红素清除血红素是一种新颖的方法，用于治疗 HIV 相关疼痛的非阿片类药物。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

High Heme and Low Heme Oxygenase-1 Are Associated with Mast Cell Activation/Degranulation in HIV-Induced Chronic Widespread Pain.

高血红素和低血红素加氧酶 1 与 HIV 引起的慢性广泛疼痛中的肥大细胞激活/脱颗粒相关。

DOI：
发表时间：
2023-06-03
期刊：
影响因子：
0
作者：
Chatterjee, Tanima;Arora, Itika;Underwood, Lilly;Gryshyna, Anastasiia;Lewis, Terry L;Masjoan Juncos, Juan Xavier;Goodin, Burel R;Heath, Sonya;Aggarwal, Saurabh
通讯作者：
Aggarwal, Saurabh

Heme-Induced Macrophage Phenotype Switching and Impaired Endogenous Opioid Homeostasis Correlate with Chronic Widespread Pain in HIV.

血红素诱导的巨噬细胞表型转换和内源性阿片类药物稳态受损与艾滋病毒慢性广泛疼痛相关。

DOI：
发表时间：
2023-06-06
期刊：
影响因子：
6
作者：
Chatterjee, Tanima;Arora, Itika;Underwood, Lilly B;Lewis, Terry L;Masjoan Juncos, Juan Xavier;Heath, Sonya L;Goodin, Burel R;Aggarwal, Saurabh
通讯作者：
Aggarwal, Saurabh

Mitochondrial network dynamics in pulmonary disease: Bridging the gap between inflammation, oxidative stress, and bioenergetics.

肺部疾病中的线粒体网络动力学：弥合炎症、氧化应激和生物能学之间的差距。

DOI：
发表时间：
2024-04
期刊：
影响因子：
11.4
作者：
Pokharel, Marissa D;Garcia;Marciano, David;Franco, Maria C;Fineman, Jeffrey R;Aggarwal, Saurabh;Wang, Ting;Black, Stephen M
通讯作者：
Black, Stephen M

Sex-Based Disparities in Leukocyte Migration and Activation in Response to Inhalation Lung Injury: Role of SDF-1/CXCR4 Signaling.

吸入性肺损伤反应中白细胞迁移和激活的性别差异：SDF-1/CXCR4 信号传导的作用。

DOI：
发表时间：
2023-06-26
期刊：
影响因子：
6
作者：
Chatterjee, Tanima;Lewis, Terry L;Arora, Itika;Gryshyna, Anastasiia E;Underwood, Lilly;Masjoan Juncos, Juan Xavier;Aggarwal, Saurabh
通讯作者：
Aggarwal, Saurabh

Assessment of pain-related behaviors in HIV-1 transgenic rats as a model of HIV-associated chronic pain.

作为 HIV 相关慢性疼痛模型，评估 HIV-1 转基因大鼠的疼痛相关行为。