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.

项目摘要/摘要冒险和获得新疗法的机会已引起人类免疫缺陷病毒（HIV）的感染慢性疾病，使患者的预期寿命几乎正常。但是，慢性病的患病率感染HIV的个体的宽度疼痛（CWP）很高，范围从25％到85％，需要低病毒负荷和足够的CD4计数。 CWP是艾滋病毒感染最常见的合并症之一，是与高残疾率和改善生活质量有关。但是，具体机制为HIV中的CWP做出贡献不了解。那就是药物和非药理学方法减轻CWP的好处很小，导致对阿片类药物的过度依赖和令人震惊和用药过量。该提议的总体目的是解决发病机理的差距 CWP并识别潜在的生物标志物和治疗靶标，以减轻HIV中的CWP。具体来说，我们会的探索无细胞血红素在损害内源性阿片类药物合成/释放中的作用 CWP HIV患者的白细胞。我们新颖的初步发现表明，自我自我的艾滋病毒患者报告具有CWP的报道升高血浆无细胞血红素水平，再加上改善的白细胞β- 内啡肽水平，相对于没有CWP的HIV患者。血红素是一种促炎的分子，可以诱导内质网应激以及白细胞的抑制功能。血红素还促进M0的过渡巨噬细胞朝着M1样促炎性而不是M2样的前型表型。与M2相比细胞，M1巨噬细胞含有并释放较低量的阿片类肽。因此，我们假设无细胞血红素可降低内源性阿片类肽依赖性镇痛，并增强PWH中的疼痛敏感性。我们将通过解决以下特定目的来实现我们的整体目标：1）建立直接链接无细胞血红素和周围内源性阿片类药物的血浆浓度与定量 HIV患者的感官度量，2）以翻译方式确定机制通过血红素有助于减少外周的阿片类药物释放和疼痛，以及3）测试血红素是否清除是增加白细胞内源性阿片类药物并减轻疼痛超敏反应的治疗选择。这项工作是新颖的，因为内源性阿片类肽合成和白细胞对CWP的释放的影响从来没有直接检查。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，以识别潜在的生物标志物和CWP在HIV中的机制。拟议的研究很重要，因为，如果我们的假设得到确认，我们将确定：1）血红素是艾滋病毒疼痛的主要驱动力，2）血红素被血红素作为一种小说，用于HIV相关疼痛的非阿片类药物治疗。

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.

DOI：
10.3390/antiox12061213
发表时间：
2023-06-03
期刊：
ANTIOXIDANTS
影响因子：
7
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

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

DOI：
10.1177/17448069231213554
发表时间：
2023-01
期刊：
Molecular pain
影响因子：
3.3
作者：
通讯作者：

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

DOI：
10.3390/cells12131719
发表时间：
2023-06-26
期刊：
CELLS
影响因子：
6
作者：
Chatterjee, Tanima;Lewis, Terry L. L.;Arora, Itika;Gryshyna, Anastasiia E. E.;Underwood, Lilly;Masjoan Juncos, Juan Xavier;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.

DOI：
10.3390/cells12121565
发表时间：
2023-06-06
期刊：
CELLS
影响因子：
6
作者：
Chatterjee, Tanima;Arora, Itika;Underwood, Lilly B.;Lewis, Terry L.;Juncos, Juan Xavier Masjoan;Heath, Sonya L.;Goodin, Burel R.;Aggarwal, Saurabh
通讯作者：
Aggarwal, Saurabh