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

• 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
• 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

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).

项目摘要 使人衰弱的疼痛是组织损伤和神经病变的标志，是一个未得到满足的临床挑战，特别是在 肌肉骨骼疾病，如异位骨化（HO）。骨科手术后可能发生HO 和创伤性损伤，表现为肌肉和结缔组织中的病理性骨形成。然而，在这方面， 在开发针对HO或其相关疼痛的有效治疗方面几乎没有取得进展。 持续性神经病理性疼痛可由背根感觉神经元伤害感受器的过度兴奋引起 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神经支配组织损伤后。骨内稳态和骨代谢之间的关键联系 在缺乏Trpv 1+的小鼠中， 伤害感受器虽然HO形成或HO相关疼痛的机制尚不清楚， 重要的见解来自于对遗传性HO亚群（即骨化性纤维发育不良）的研究 Progressiva（FOP）。FOP通常是由一个组氨酸206到组氨酸的功能获得性点突变引起的， BMP I型受体（ACVR 1，也称为ALK 2）在97%的患者中。我们最近发现， FOP患者有基线热和机械超敏反应，在没有炎性反应的情况下， 突然爆发利用FOP患者诱导的多能干细胞（iPSC）衍生的伤害感受感觉神经元 （iSN），我们证明了ACVR 1 R206 H是必要的，也是足够的过度兴奋， 伤害感受器神经性疼痛的标志为了确定神经元ACVR 1过度活跃是否也是 与更常见的神经病理性疼痛状况相关，我们条件性地表达了激活性Acvr 1 R206 H。 非FOP转基因小鼠的感觉神经元。这导致了一个显着的重演的机械和 FOP患者的热超敏反应。由于Acvr 1表达在轴突切断的DRG中显著增加， 我们发现，在传统的神经病理性疼痛的临床前模型中， 通过鞘内（IT）注射一种抑制DRG中损伤诱导的活性神经元ACVR 1信号传导的药物， 小分子ACVR 1/ALK 2激酶抑制剂可预防损伤诱导的机械超敏反应， 重要的是，逆转了小鼠SNI模型中的持续性疼痛。根据我们的观察， 在FOP的临床前小鼠模型中，HO引发了大量伤害感受器在损伤部位的发芽，我们进一步研究了HO的作用。 假设感觉神经元中的活性ACVR 1信号传导是神经病理性疼痛和 何总之，旨在阐明活性ACVR 1信号传导的下游机制， 可能与其他慢性疼痛和肌肉骨骼损伤情况相同;同时开发新的治疗方法 策略，我们将定义感觉神经元特异性ACVR 1的分子靶点， 疼痛（目标1）;验证抑制外周神经元ACVR 1是否会降低超敏反应（目标2）;并确定 感觉神经元特异性ACVR 1是否有助于损伤诱导的HO（目的3）。