Determining the pathogenicity of genetic variants in pain-associated genes: Establishment of a refined protocol for patient-derived nociceptors and personalized application in chronic pain patients
确定疼痛相关基因遗传变异的致病性:建立患者源性伤害感受器的精细方案并在慢性疼痛患者中进行个性化应用
基本信息
- 批准号:461440976
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:
- 资助国家:德国
- 起止时间:
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Screening for genetic alterations in pain-associated genes is increasingly performed in patients with pain syndromes of so far idiopathic origin and often results in findings that remain of unclear pathogenicity. Given their diagnostic, therapeutic, and prognostic uncertainty, these findings are a great challenge for treating physicians and patients. The only possibility to unravel if such variations are of clinical relevance is by investigating patient-derived nociceptors which may be generated via induced pluripotent stem cells (iPSC). This methodology, however, carries the limitation of almost uncontrollable cellular heterogeneity after neuron differentiation. This heterogeneity renders the application of cell-specific analysis impossible and also dramatically reduces the significance of the obtained data. In our translational project, we will meet these exact two challenges. By genetic screening of a comprehensively characterized patient cohort with chronic pain based on small fiber pathology, we will identify patients carrying genetic variants of so far unknown pathogenicity and will generate individual sensory neurons via iPSC. Combining specific staining techniques, differential FACS analysis, and electrophysiological characterization, we will isolate nociceptors that will allow personalized RNA sequencing which is currently hampered by cellular heterogeneity upon neuronal differentiation. Following a multidimensional approach and by integrative data analysis considering clinical phenotype and in vitro data, we will identify and characterize novel pathogenic variants in pain-associated genes and will provide treating physicians phenotypic features for clinical usage; further, we will formulate a refined protocol to specifically spot nociceptors among iPSC-derived sensory neurons in basic science. This translational project bears the immense potential to enrich and improve clinical and basic pain research by fresh perspectives and knowledge with sustainable impact on pain diagnostics, treatment, and prevention.
在疼痛相关基因的遗传变异筛查越来越多地进行到目前为止,原发性疼痛综合征的患者,往往导致的结果,仍然是不清楚的致病性。鉴于其诊断、治疗和预后的不确定性,这些发现对治疗医生和患者都是一个巨大的挑战。如果这种变化具有临床相关性,唯一的可能性是通过研究可能通过诱导多能干细胞(iPSC)产生的患者来源的伤害感受器。然而,这种方法具有神经元分化后几乎无法控制的细胞异质性的局限性。这种异质性使得细胞特异性分析的应用不可能,并且还显著降低了所获得的数据的重要性。在我们的翻译项目中,我们将满足这两个挑战。通过对基于小纤维病理学的慢性疼痛的综合特征患者队列进行遗传筛查,我们将识别携带迄今未知致病性的遗传变异的患者,并将通过iPSC产生个体感觉神经元。结合特异性染色技术,差分流式细胞仪分析,和电生理学表征,我们将分离伤害感受器,这将允许个性化的RNA测序,这是目前阻碍了细胞异质性神经元分化。遵循多维方法并通过综合数据分析考虑临床表型和体外数据,我们将识别和表征疼痛相关基因中的新型致病性变体,并将为临床使用提供治疗医生的表型特征;此外,我们将制定一个完善的方案,以在基础科学中特异性地发现iPSC衍生的感觉神经元中的伤害感受器。这个翻译项目具有丰富和改善临床和基础疼痛研究的巨大潜力,通过新的观点和知识对疼痛诊断,治疗和预防产生可持续的影响。
项目成果
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Professorin Dr. Nurcan Üçeyler其他文献
Professorin Dr. Nurcan Üçeyler的其他文献
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{{ truncateString('Professorin Dr. Nurcan Üçeyler', 18)}}的其他基金
Translational analysis of the mechanisms underlying small nerve fiber pathology in Fabry disease as a genetically determined model for neuropathic pain
法布里病小神经纤维病理学机制的转化分析作为神经性疼痛的遗传决定模型
- 批准号:
392463150 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Research Grants
Role of cholinergic signaling and its controlling regulatory genes in the pathophysiology of pain in fibromyalgia syndrome
胆碱能信号及其控制调节基因在纤维肌痛综合征疼痛病理生理学中的作用
- 批准号:
323267254 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Research Grants
Investigation of the growth-modulating and axon-sensitizing effect of keratinocytes and fibroblasts on intraepidermal nerve fibers
角质形成细胞和成纤维细胞对表皮内神经纤维的生长调节和轴突敏化作用的研究
- 批准号:
280178488 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Research Grants
Translational and multidimensional analysis of the mechanisms underlying nociceptor sensitization in small fiber pathology
小纤维病理学中伤害感受器敏化机制的转化和多维分析
- 批准号:
523633805 - 财政年份:
- 资助金额:
-- - 项目类别:
Research Grants
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