The Role of GDNF Family Ligands in Itch

GDNF 家族配体在瘙痒中的作用

• 批准号: 8783883
• 负责人: Manouela Vesselinova Valtcheva
• 金额: $ 2.67万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-09 至 2016-05-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783883
• 关键词: Acute; Address; Affect; Afferent Neurons; Animal Behavior; Atopic Dermatitis; Autoimmune Process; Behavior; Behavioral Model; Biochemistry; Calcium; Caliber; Cell physiology; Cells; Chloroquine; Chronic; Data; Development; Esthesia; Family; Fellowship; Fiber; Figs - dietary; GDNF gene; GDNF receptors; Genetic; Histamine; Hour; Image; Immunohistochemistry; Knockout Mice; Label; Left; Ligands; Maintenance; Measures; Mediator of activation protein; Membrane; Microscopy; Modeling; Morphology; Mus; Nerve Fibers; Neurologic; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 1; Pain; Pathway interactions; Patients; Peripheral Nerves; Pharmaceutical Preparations; Physicians; Physiology; Play; Population; Pruritus; Psoriasis; Quality of life; Receptor Protein-Tyrosine Kinases; Reporter; Role; Scientist; Signal Transduction; Skin; Structure; Structure of trigeminal ganglion; Symptoms; TRPA1 Channel; TRPV1 gene; Tamoxifen; Techniques; Testing; Training; Translational Research; Trigeminal System; Work; base; clinically relevant; density; effective therapy; experience; mouse model; nerve supply; neuron development; neurotrophic factor; neurturin; novel; public health relevance; receptor expression; receptor function; response

DESCRIPTION (provided by applicant): Chronic itch affects up to 15% of the population but is poorly controlled with currently available treatments. Pruriceptors are small diameter nerve fibers that innervate the skin and transduce itch. While several histamine-dependent and histamine-independent itch pathways have been discovered, little is known about how chronic itch develops. Studies of patients with atopic dermatitis and psoriasis indicate that increased epidermal innervation and increased levels of neurotrophic factors may be involved. Most pruriceptors express Ret, the receptor for GDNF-family ligands (GFLs), but no studies have investigated the role of GFL-Ret signaling in pruriceptor function. Our preliminary data indicate that Ret+ epidermal fibers are increased in a model of dry skin itch. Furthermore, we have found that pretreatment with artemin (a GFL) significantly potentiates scratching behavior and neuronal responses to the pruritogen chloroquine. Based on these findings, we hypothesize that GFLs modulate pruriceptor structure and function. In Aim 1 of this proposal we will determine if GFLs can induce itch or modulate pruritogen-induced scratching. We will also determine if chronic treatment with GFLs induces epidermal hyperinnervation and whether these changes correlate with increases in scratching behavior. In Aim 2, we will utilize RetEGFP/+ reporter mice and retrograde labeling to determine the direct effects of artemin on pruritogen receptor expression and function by recording calcium responses in dissociated trigeminal ganglion neurons. In Aim 3, we will use tamoxifen-inducible sensory neuron-specific Ret conditional knock-out mice (Ret-cKOs) to determine if endogenous Ret signaling is important for normal pruriceptor expression and function. We will also determine if Ret expression is necessary for GFL-induced effects on itch. The work generated by this proposal will ultimately determine whether GFLs are potential targets for the treatment of chronic pruritus.

描述(申请人提供)：慢性瘙痒影响高达15%的人口，但目前可用的治疗方法控制不佳。瘙痒感受器是一种小直径的神经纤维，它支配皮肤并传导瘙痒。虽然已经发现了几种组胺依赖和组胺非依赖的瘙痒途径，但对慢性瘙痒是如何发展的知之甚少。对特应性皮炎和银屑病患者的研究表明，表皮神经支配的增加和神经营养因子水平的增加可能与此有关。大多数瘙痒感受器表达胶质细胞源性神经营养因子家族配体的受体Ret，但尚未有研究探讨GFL-Ret信号在瘙痒感受器功能中的作用。我们的初步数据表明，在干性皮肤瘙痒模型中，Ret+表皮纤维增加。此外，我们还发现，用青蒿素(一种GFL)预处理显著增强了抓挠行为和对瘙痒原氯喹的神经元反应。基于这些发现，我们假设GFLS调节瘙痒感受器的结构和功能。在这项提案的目标1中，我们将确定GFLS是否可以诱导瘙痒或调节瘙痒原诱导的抓挠。我们还将确定长期使用GFLS是否会诱导表皮过度神经支配，以及这些变化是否与抓挠行为的增加有关。在目标2中，我们将利用RetEGFP/+报告小鼠和逆行标记，通过记录三叉神经节分离神经元的钙反应来确定青蒿素对瘙痒原受体表达和功能的直接影响。在目标3中，我们将使用他莫昔芬诱导的感觉神经元特异性Ret条件性敲除小鼠(Ret-cKO)来确定内源性Ret信号对正常的瘙痒感受器表达和功能是否重要。我们还将确定Ret的表达是否对GFL诱导的瘙痒效应是必要的。这项提案所产生的工作将最终确定GFLS是否为治疗慢性瘙痒的潜在靶点。