ACVR1 sensory neuron-specific signaling in neuropathic pain and injury-induced heterotopic ossification

ACVR1 感觉神经元特异性信号在神经病理性疼痛和损伤诱导的异位骨化中的作用

基本信息

批准号：
10737041
负责人：
Xiaobing Yu
金额：
$ 52.12万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737041
关键词：
ACVR1 gene Adult Afferent Neurons Axotomy Biological Assay Cells Clinical Connective Tissue Genes Heterotopic Ossification Histidine Homeostasis Hyperactivity Hypersensitivity Immune Immune response Impairment In Vitro Inflammatory Inherited Injury Intrathecal Injections Link Macrophage Mechanics Modeling Molecular Molecular Target Mus Muscle Musculoskeletal Diseases Neuroimmune Neurons Neuropathy Neuropeptides Nociception Nociceptors Orthopedic Surgery Osteogenesis Pain Pathologic Patients Peripheral Persistent pain Physiologic Ossification Point Mutation Pre-Clinical Model Signal Transduction Site Spinal Ganglia Surgical Injuries Testing Therapeutic Tissues Transgenic Mice Trauma Traumatic injury bone bone loss bone morphogenetic protein receptor type I chronic pain debilitating pain effective therapy gain of function in vivo Model induced pluripotent stem cell inhibitor insight kinase inhibitor mouse model musculoskeletal injury nerve injury novel novel strategies novel therapeutic intervention pain model painful neuropathy phase II trial pre-clinical prevent progressive myositis ossificans release factor response small molecule spared nerve tissue injury transcriptomic profiling transcriptomics

项目摘要

PROJECT SUMMARY Debilitating pain, a hallmark of tissue injury and neuropathy, is an unmet clinical challenge particularly in musculoskeletal diseases, such as heterotopic ossification (HO). HO can occur following orthopedic surgery and traumatic injuries, manifests with pathological bone formation in muscle and connective tissues. However, little progress has been made in developing effective treatments for either HO or its associated pain. Persistent neuropathic pain can arise from hyperexcitability of sensory neuron nociceptors in dorsal root ganglia (DRG), which release neuropeptides, interact with immune cells, and modulate the host response after injury to innervated tissues including bone and muscle. A critical link between bone homeostasis and neuropathic pain has been suggested by the impaired ossification and bone loss in mice lacking Trpv1+ nociceptors. Although the mechanisms that underlie HO formation or HO related pain are poorly understood, important insights derive from studies of an hereditary HO subset, namely Fibrodysplasia Ossificans Progressiva (FOP). FOP is commonly caused by an arginine206 to histidine gain-of-function point mutation in the BMP type I receptor (ACVR1, also known as ALK2) in 97% of patients. We recently found that adult patients with FOP have baseline heat and mechanical hypersensitivity, in the absence of an inflammatory flareup. Utilizing FOP patient induced pluripotent stem cell (iPSC)-derived nociceptive sensory neurons (iSNs), we demonstrated that ACVR1R206H is both necessary and sufficient for the hyperexcitability of nociceptors, a hallmark of neuropathic pain. To determine whether neuronal ACVR1 hyperactivity is also relevant to more common neuropathic pain conditions, we conditionally expressed activating Acvr1R206H in sensory neurons of non-FOP transgenic mice. This led to a remarkable recapitulation of the mechanical and heat hypersensitivity in patients with FOP. As Acvr1 expression is profoundly increased in axotomized DRG neurons in a traditional preclinical model of neuropathic pain produced by spared nerve injury (SNI), we found that inhibiting injury-induced active neuronal ACVR1 signaling in the DRG by intrathecal (IT) injections of a small-molecule ACVR1/ALK2 kinase inhibitor prevented injury-induced mechanical hypersensitivity and, most importantly, reversed persistent pain in the mouse SNI model. Based on our observation that trauma-induced HO triggered massive nociceptor sprouting at the injury site in a preclinical mouse model of FOP, we further hypothesize that active ACVR1 signaling in sensory neurons is a critical link between neuropathic pain and HO. Together, aiming to elucidate the mechanisms downstream of active ACVR1 signaling, mechanisms that may be shared by other chronic pain and musculoskeletal injury conditions; while developing new treatment strategies, we will define molecular targets of sensory neuron-specific ACVR1 that contribute to neuropathic pain (Aim 1); validate if inhibiting peripheral neuronal ACVR1 reduces hypersensitivity (Aim 2); and determine if sensory neuron-specific ACVR1 contributes to injury-induced HO (Aim 3).

项目概要衰弱性疼痛是组织损伤和神经病变的标志，是一个尚未解决的临床挑战，特别是在肌肉骨骼疾病，例如异位骨化（HO）。 HO 可能发生在骨科手术后和外伤，表现为肌肉和结缔组织中的病理性骨形成。然而，在开发针对 HO 或其相关疼痛的有效治疗方法方面进展甚微。持续性神经病理性疼痛可能是由背根感觉神经元伤害感受器过度兴奋引起的神经节 (DRG)，释放神经肽、与免疫细胞相互作用并调节宿主反应包括骨骼和肌肉在内的受神经支配的组织受伤后。骨稳态与骨代谢之间的重要联系缺乏 Trpv1+ 的小鼠的骨化受损和骨质流失表明存在神经性疼痛伤害感受器。尽管人们对 HO 形成或 HO 相关疼痛的机制知之甚少，重要的见解源自对遗传性 HO 子集（即骨化纤维发育不良）的研究进步（FOP）。 FOP 通常是由 206 位精氨酸变为组氨酸的功能获得性点突变引起的 97% 的患者存在 I 型 BMP 受体（ACVR1，也称为 ALK2）。我们最近发现成人 FOP 患者在没有炎症的情况下具有基线热和机械超敏反应爆发。利用 FOP 患者诱导多能干细胞 (iPSC) 衍生的伤害性感觉神经元（iSNs），我们证明了 ACVR1R206H 对于神经元的过度兴奋来说既是必要的也是充分的伤害感受器，神经性疼痛的标志。确定神经元 ACVR1 过度活跃是否也与与更常见的神经病理性疼痛相关，我们有条件地表达激活 Acvr1R206H 非 FOP 转基因小鼠的感觉神经元。这导致了机械和 FOP 患者的热过敏症。由于 Acvr1 表达在轴突 DRG 中显着增加我们发现，在由幸存神经损伤（SNI）产生的神经病理性疼痛的传统临床前模型中，神经元通过鞘内 (IT) 注射一种药物来抑制 DRG 中损伤诱导的活性神经元 ACVR1 信号传导小分子 ACVR1/ALK2 激酶抑制剂可预防损伤引起的机械超敏反应，并且大多数重要的是，逆转了小鼠 SNI 模型中的持续疼痛。根据我们的观察，创伤引起的在 FOP 临床前小鼠模型中，H2O 引发损伤部位大量伤害感受器萌芽，我们进一步假设感觉神经元中的活跃 ACVR1 信号传导是神经性疼痛和何。总之，旨在阐明主动 ACVR1 信号传导的下游机制，这些机制可能还有其他慢性疼痛和肌肉骨骼损伤病症；在开发新疗法的同时策略，我们将定义感觉神经元特异性 ACVR1 的分子靶标，这些靶标有助于神经病疼痛（目标 1）；验证抑制周围神经元 ACVR1 是否可以降低超敏反应（目标 2）；并确定感觉神经元特异性 ACVR1 是否有助于损伤诱导的 HO（目标 3）。