Cellular senescence in chronic pain and aging

慢性疼痛和衰老中的细胞衰老

• 批准号: 10672987
• 负责人: Vivianne L Tawfik
• 金额: $ 19.82万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10672987
• 关键词: Acute; Address; Adult; Adverse effects; Affect; Affective; Afferent Neurons; Aftercare; Age; Aging; Agonist; American; Animal Model; Animals; Anxiety; Basic Science; Behavioral; Behavioral Paradigm; CCL2 gene; Calcium; Capsaicin; Cell Aging; Cells; Chronic; Clinical Trials; Data; Development; Disease; Dissociation; Elderly; Electrophysiology (science); Evaluation; Future; Heterogeneity; Homeostasis; Human; Hypersensitivity; IL6 gene; Image; Immunohistochemistry; In Situ Hybridization; In Vitro; Individual; Induction of Apoptosis; Inflammation; Inflammatory; Injury; Interleukin-1 beta; Ipsilateral; Knowledge; Label; Measures; Mediator; Medical; Medicine; Memory; Molecular; Mus; Neuronal Injury; Neurons; Nociceptors; Pain; Peripheral; Peripheral nerve injury; Persistent pain; Pharmaceutical Preparations; Phenotype; Physicians; Population; Predisposition; Research; Risk; Risk Factors; Rodent; Scientist; Sensory; Societies; Source; Spinal Ganglia; TNF gene; TP53 gene; Testing; Time; Tissues; Work; activating transcription factor 3; age related; aged; cell type; chronic pain; chronic pain management; chronic pain patient; chronic painful condition; comorbidity; cost; cytokine; effectiveness evaluation; experimental study; high reward; high risk; human old age (65+); improved; in vivo; individualized medicine; injured; mechanical allodynia; molecular marker; mouse model; nerve injury; neuronal cell body; neuronal excitability; novel therapeutics; pain behavior; pain outcome; painful neuropathy; paracrine; postmitotic; pre-clinical; release factor; response; senescence; side effect; spared nerve; synergism; two-photon; young adult

Project Summary Chronic pain is a debilitating condition from which one in three Americans suffer, at a high cost to society. Aging is a major risk factor for the development of chronic pain with 50% of adults over the age of 65 suffering from at least one chronic pain condition. Unfortunately, it is not well understood why age is a risk factor for the development of pain conditions. Thus, there is an urgent need for basic research using aged animal models to examine the underlying interaction between age and pain and ultimately inform the development of tailored treatments for this specific population. As humans and animals age, senescent cells accumulate in many tissues throughout the body and disrupt tissue homeostasis by secreting factors that induce inflammation, known as senescence-associated secretory phenotype (SASP). Interestingly, several of these SASP factors are known pain-inducing cytokines that are released in the dorsal root ganglion (DRG), where primary sensory neuron cell bodies reside, and drive pain. Surprisingly, senescent cells have yet to be investigated within the pain circuit in aged mice, or even in young mice after peripheral nerve injury. We hypothesize that senescent cells; 1) are present in the pain circuit of aged mice, 2) further accumulate following nerve injury, and 3) contribute to chronic reflexive and affective pain responses through secretion of SASP factors. In support of our hypothesis, we have robust preliminary data demonstrating a 4-fold increase in senescent neurons in uninjured aged DRG compared to uninjured young DRG. Additionally, we demonstrate expression of the early senescence marker, p21, in injured (ATF3+) and uninjured (ATF3-) populations of Trpv1+ nociceptive neurons, suggesting paracrine induction of senescence. We localize the SASP factor and pain mediator, IL6, to these p21+ cells providing evidence that senescent cells are a cellular source of such factors in the pain circuit. Finally, we have preliminary data that indicate treatment with a senolytic drug improves spared nerve injury (SNI)-induced mechanical allodynia while maintaining overall sensory function in young adult and aged mice. Therefore, a potential mechanism underlying enhanced pain hypersensitivity following injury in aged mice may be the combination of age-related and injury- induced senescent cells. In this proposal, we aim to further characterize senescent cell induction following SNI by analyzing the co-expression of senescent markers within individual cells, determining their specific cellular identities, and quantifying SASP factor expression, at baseline (uninjured) and at acute and chronic post-injury time points in young and aged mice. Further, we will investigate the senescent cell contribution to neuronal hyperexcitability in vitro using 2-photon calcium imaging and electrophysiology, as well as in vivo using pain behavioral paradigms in aged mice compared to young adult mice after treatment with specific senolytic agents, which may selectively induce apoptosis of subtypes of senescent cells in the DRG. This research will be the first of its kind to investigate cellular senescence in a pre-clinical mouse model of neuropathic pain and has the potential to open a new therapeutic avenue, using senolytic agents, to alleviate pain.

项目摘要 慢性疼痛是一种令人衰弱的状况，三分之一的美国人遭受了痛苦，以高昂的成本造成社会。老化 是慢性疼痛发展的主要危险因素，有50％的65岁以上的成年人患有AT 至少一个慢性疼痛状况。不幸的是，尚不清楚为什么年龄是 疼痛状况的发展。因此，迫切需要使用老年动物模型的基础研究 检查年龄和疼痛之间的潜在互动，并最终告知量身定制的发展 针对该特定人群的治疗。随着人类和动物的年龄，衰老细胞在许多组织中积累 在整个身体中，通过分泌引起炎症的因素来破坏组织稳态，称为 衰老相关的分泌表型（SASP）。有趣的是，其中几个SASP因素是已知的 在背根神经节（DRG）中释放的疼痛诱导细胞因子，其中主要感觉神经元细胞 尸体居住，疼痛。令人惊讶的是，在疼痛回路中尚未研究衰老细胞 外周神经损伤后，年龄的小鼠，甚至在年轻小鼠中。我们假设衰老细胞。 1）是 存在于老年小鼠的疼痛回路中，2）在神经损伤后进一步积累，3）有助于慢性 通过分泌SASP因素，反思性和情感疼痛反应。为了支持我们的假设，我们有 强大的初步数据表明，在不伤害的DRG中，衰老神经元增加了4倍 要犯下的年轻DRG。此外，我们证明了早期衰老标记P21的表达 受伤（ATF3+）和未受伤的TRPV1+伤害性神经元的群体，表明旁分泌诱导 衰老。我们将SASP因子和止痛介质IL6定位于这些P21+细胞，提供了证据表明 衰老细胞是疼痛回路中此类因素的细胞来源。最后，我们有初步数据 表明用鼻溶剂治疗可改善免受神经损伤（SNI）诱导的机械性异常性疾病，而 保持年轻小鼠和老年小鼠的总体感觉功能。因此，一种潜在的机制 老年小鼠损伤后疼痛超敏反应增强可能是与年龄有关的损伤和损伤的组合 诱导的衰老细胞。在此提案中，我们旨在进一步表征SNI后的衰老细胞诱导 通过分析单个细胞内衰老标记的共表达，确定其特异性细胞 在基线（未受伤）和急性和慢性后，身份和量化SASP因子表达 年轻小鼠的时间点。此外，我们将研究对神经元的衰老细胞贡献 使用2光子钙成像和电生理学以及体内使用疼痛的体外过度兴奋 与特定的鼻溶剂治疗后，与年轻小鼠相比，老年小鼠的行为范例， 这可能会选择性诱导DRG中衰老细胞亚型的凋亡。这项研究将是第一个 在神经性疼痛的临床前小鼠模型中研究细胞衰老的同类 使用塞溶剂剂来减轻疼痛的潜力开放新的治疗大道。