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.

项目概要 慢性疼痛是一种使人衰弱的疾病，三分之一的美国人患有这种疾病，给社会造成了高昂的代价。老化 是形成慢性疼痛的主要危险因素，50% 的 65 岁以上成年人患有 至少一种慢性疼痛状况。不幸的是，目前尚不清楚为什么年龄是该病的危险因素。 疼痛状况的发展。因此，迫切需要利用老年动物模型进行基础研究 研究年龄和疼痛之间潜在的相互作用，并最终为定制的开发提供信息 针对这一特定人群的治疗。随着人类和动物的衰老，衰老细胞在许多组织中积累 遍布全身并通过分泌诱发炎症的因子破坏组织稳态，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 背根神经节 (DRG) 中释放的诱发疼痛的细胞因子，初级感觉神经元细胞 身体驻留，并驱使疼痛。令人惊讶的是，衰老细胞在疼痛回路中的作用尚未得到研究。 老年小鼠，甚至周围神经损伤后的年轻小鼠。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）导致慢性疼痛 通过分泌 SASP 因子产生反射性和情感性疼痛反应。为了支持我们的假设，我们有 可靠的初步数据表明，与未受伤的老年 DRG 相比，衰老神经元增加了 4 倍 到未受伤的年轻DRG。此外，我们还证明了早期衰老标志物 p21 在 受伤（ATF3+）和未受伤（ATF3-）Trpv1+伤害性神经元群体，表明旁分泌诱导 的衰老。我们将 SASP 因子和疼痛介质 IL6 定位于这些 p21+ 细胞，提供了以下证据： 衰老细胞是疼痛回路中此类因子的细胞来源。最后，我们得到了初步数据 表明使用 senolytics 药物治疗可改善幸存神经损伤 (SNI) 引起的机械异常性疼痛，同时 维持年轻成年和老年小鼠的整体感觉功能。因此，潜在的机制 老年小鼠受伤后疼痛超敏反应增强可能是年龄相关和损伤的结合。 诱导衰老细胞。在本提案中，我们的目标是进一步表征 SNI 后的衰老细胞诱导 通过分析单个细胞内衰老标志物的共表达，确定其特定的细胞 基线（未受伤）以及急性和慢性损伤后的身份，并量化 SASP 因子表达 年轻和老年小鼠的时间点。此外，我们将研究衰老细胞对神经元的贡献 使用 2 光子钙成像和电生理学在体外以及使用疼痛进行体内过度兴奋 用特定的衰老剂治疗后，老年小鼠的行为模式与年轻的成年小鼠相比， 可能选择性诱导DRG中衰老细胞亚型的凋亡。这项研究将是第一个 此类研究用于研究临床前神经性疼痛小鼠模型中的细胞衰老，并具有 有潜力开辟一条新的治疗途径，使用抗衰老药物来减轻疼痛。