Alleviation of chronic TBI through modulation of calcium signaling

通过调节钙信号传导缓解慢性 TBI

• 批准号: 10700780
• 负责人: Bidhan Chandra Bandyopadhyay
• 金额: --
• 依托单位: U.S. DEPT/VETS AFFAIRS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700780
• 关键词: Affect; Afghanistan; Agonist; Anterior Pituitary Gland; Anxiety; Area; Attenuated; Behavior; Behavioral; Botulinum Toxins; Brain; Brain region; Calcium Signaling; Calcium ion; Cell Survival; Cells; Chronic; Clinical; Complex; Data; Disease; Fatigue; Feedback; Functional disorder; Future; Genetic; Goals; Hormonal; Hormone replacement therapy; Hormone secretion; Hormones; Hypopituitarism; Hypothalamic structure; Image; Impaired cognition; Impairment; Inflammation; Inflammatory Response; Injury; Investigation; Ion Channel; Iraq; Measures; Mediating; Medical; Memory; Memory impairment; Mental Depression; Modeling; Molecular; Mus; Natural regeneration; Neuronal Injury; Neurons; Neurosecretory Systems; Outcome; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pituitary Gland; Posttraumatic growth; Process; Proteins; Publishing; Quality of life; Rattus; Reagent; Recovery; Rehabilitation therapy; Research Personnel; Resources; Role; SNAP receptor; Series; Serum; Signal Transduction; Signs and Symptoms; Site; Somatostatin; Somatotropin; Somatotropin-Releasing Hormone; Survivors; Synaptic Vesicles; TBI Patients; TRP channel; Testing; Therapeutic; Time; Traumatic Brain Injury; Vesicle; Veterans; Walking; War; axon growth; axon injury; axon regeneration; behavior test; behavioral study; controlled cortical impact; experimental study; functional restoration; ghrelin; growth hormone deficiency; hypothalamic pituitary axis; improved; injured; innovation; morris water maze; motor learning; mouse model; neurobehavioral; neurochemistry; neurotropic; novel; novel therapeutics; patch clamp; pharmacologic; postsynaptic; protein complex; psychologic; receptor; repaired; restoration; side effect; targeted delivery; technology platform; tool

Project Summary: Growth hormone deficiency (GHD) due to chronic traumatic brain injury (TBI) is common among the veterans from the wars in Iraq and Afghanistan. Such condition develops as a result of hypothalamic-pituitary axis (HPA) dysfunction leading to reduced growth hormone (GH) levels, which pose a significant impact on their quality of life due to medical, psychological, and psychiatric consequences. The GH replacement therapy in post-traumatic GHD, in most cases, do not produce the desired clinical outcome. Analysis of the signs and symptoms of HPA dysfunction suggests that compromise in GH secretion may be as a result of defective upstream hypothalamic signaling. Thus, we propose to restore the hypothalamic- neurotropic stimulation by endogenous GH secretion from the surviving (post-TBI) anterior pituitary cells (somatotrophs), leading to axonal regeneration of TBI-damaged neurons. Although intracellular calcium ion (Ca2+) concentration ([Ca2+]i) can regulate hormone release, the ion channel responsible for increasing [Ca2+]i the GH release in pituitary somatotrophs is unknown. Our ongoing studies have identified that activation of Transient Receptor Potential Canonical 3 (TRPC3), a Ca2+ influx channel, facilitates vesicle-associated soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein complex interactions, which is necessary for hormonal release. Moreover, disruption of TRPC3 markedly attenuated [Ca2+]i entry, which is essential for GH secretion and axonal regeneration. Thus, our central hypothesis is that the agonist activation of TRPC3 in pituitary cells triggers Ca2+ entry, resulting in enhanced GH secretion, which will help to regenerate those damaged axons in the adjacent HPA region. We propose to study the following two Aims using an established controlled cortical impact (CCI)-induced injury mouse model of TBI: (1) Characterization of the role of TRPC3 in regulating GH secretion by examining the functional restoration of hypothalamic neurotropic connections in TBI; and (2) Determine that TRPC3 activation stimulates axonal regeneration in TBI-damaged neurons and examine a “proof of concept” that augmenting TRPC3 expression/activation ameliorates chronic neurobehavioral abnormalities. We will perform a series of behavioral tests such as Morris water maze for memory and beam walk test to assess sensorimotor coordination and motor learning for correlating the behavior with brain neurochemistry. The results of the present study will: i) find the novel mechanism of TRPC3-induced GH secretion essential for axonal growth and regeneration that can be used as a tool to identify potential new therapeutic options; ii) elucidate the molecular pathogenesis of GH secretion following chronic TBI; and iii) help to plan and execute future investigations to improve and manage TBI- induced GHD and neurobehavioral abnormalities in both veterans and civilians.

项目摘要：由于慢性创伤性脑损伤（TBI）引起的生长马酮缺乏症（GHD）很常见 在伊拉克和阿富汗战争的退伍军人中。由于 下丘脑 - 垂体轴（HPA）功能障碍导致生长骑马（GH）水平降低，构成A 由于医学，心理和精神科后果，对其生活质量的重大影响。 GH 在大多数情况下，创伤后GHD的替代疗法不会产生所需的临床结果。 HPA功能障碍的体征和症状的分析表明，GH分泌的妥协可能是 上游下丘脑信号传导的结果。这，我们建议恢复下丘脑 - 从幸存的（TBI后）前偏向细胞中内源性GH分泌的神经性刺激 （躯体营养），导致TBI受损神经元的轴突再生。虽然细胞内钙离子 （Ca2+）浓度（[Ca2+] i）可以调节马酮释放，这是负责增加[Ca2+] I的离子通道 垂体间营养中的GH释放尚不清楚。我们正在进行的研究已经确定 瞬态受体电势典型3（TRPC3），一个Ca2+影响通道，促进了囊泡相关的可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）蛋白复合物相互作用，这是 激素释放所需的必要。此外，TRPC3的破坏显着减弱[Ca2+] I条目， GH分泌和轴突再生必不可少的。那就是我们的中心假设是激动剂激活 trpc3在熟练细胞中触发Ca2+​​进入，从而增强了GH分泌，这将有助于 在邻近的HPA区域再生那些受损的轴突。我们建议研究以下两个目标 使用已建立的受控皮质冲击（CCI）诱导的TBI损伤小鼠模型：（1）表征 通过检查下丘脑的功能恢复，TRPC3在调节GH分泌中的作用 TBI中的神经性连接； （2）确定TRPC3激活刺激轴突再生 TBI受损的神经元并检查了增强TRPC3表达/激活的“概念证明” 改善慢性神经行为异常。我们将执行一系列行为测试，例如莫里斯 用于记忆和梁步行测试的水迷宫，以评估感觉运动协调和运动学习 将行为与脑神经化学相关联。本研究的结果将：i）找到小说 TRPC3诱导的GH分泌的机理对于轴突生长和再生必不可少的机制，可以用作 一种识别潜在的新治疗选择的工具； ii）阐明GH分泌的分子发病机理 跟随慢性TBI； iii）帮助计划和执行未来的调查，以改善和管理TBI- 退伍军人和平民诱发的GHD和神经行为异常。