Hormonal Intervention Protects Axon-myelin to Promote Functional Recovery in SCI

激素干预保护轴突髓磷脂，促进 SCI 功能恢复

• 批准号: 10700378
• 负责人: NAREN L BANIK
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700378
• 关键词: Acute; Anti-Inflammatory Agents; Area; Astrocytes; Attenuated; Axon; Biodistribution; Bioenergetics; Bladder; Cells; Cicatrix; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Contusions; Correlative Study; Data; Denervation; Diabetes Mellitus; Dose; Drug Delivery Systems; Epithelium; Estrogens; F-Box Proteins; Fibroblasts; Formulation; Gel; General Population; Gliosis; Goals; Health; High Prevalence; Hormonal; Human; Immobilization; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Insulin Resistance; Intervention; Kinetics; Laboratories; Lesion; Limb structure; Mediating; Methylprednisolone; Microglia; Modeling; Molecular; Morphology; Motor; Motor Neurons; Muscle; Muscle Fibers; Muscle Proteins; Muscular Atrophy; Myelin; Myoblasts; Nerve; Nervous System Trauma; Neurologic Deficit; Neurologic Dysfunctions; Neuronal Dysfunction; Neurons; Neurophysiology - biologic function; Oligodendroglia; Paralysed; Patients; Penetration; Phase; Plasma; Population; Prevention; Rattus; Recovery; Recovery of Function; Rehabilitation therapy; Safety; Signal Transduction; Skeletal Muscle; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Techniques; Testing; Tissues; Toxic effect; Translations; Veterans; alternative treatment; axon injury; chemokine; combat veteran; comparative; cytokine; effective therapy; estrogenic; experience; functional outcomes; improved; in vivo; inflammatory modulation; insight; medication safety; muscle RING finger 1; myelination; nanoparticle; neuroinflammation; neuron loss; neuroprotection; novel; novel marker; pharmacologic; preservation; reduced muscle mass; research clinical testing; skeletal muscle wasting; steroid hormone; translational potential

Severe spinal cord injury (SCI) is a complex, debilitating condition leading to permanent life-long neurological deficits. In addition to neurological dysfunction, individuals with SCI experience neurogenic muscle loss due to immobility. Amelioration of neurological deficits and prevention of skeletal muscle loss are intricately related to recovery of function following SCI. Molecular mechanisms causing neuronal impairment and skeletal muscle loss resulting from SCI, remain incompletely understood. Our laboratory is among the first to demonstrate steroid hormone estrogen (E2) driven neuroprotection in experimental SCI in rats, suggesting E2 warrants clinical evaluation in individuals with neurotrauma. The beneficial effect in SCI was found at a low dose of 10μg/kg E2, but the dose remains at a non-physiologic for human use, and thereby poses a safety concern for clinical use. The emergence of smart drug delivery techniques, such as nanoparticles, may allow for increased drug safety and improved efficacy. Thus, the goal of this proposal is to examine the effects of novel fast and slow release E2-loaded nanoparticles (NP) on neuronal dysfunction and skeletal muscle loss in a rat contusion model of SCI. Since muscle loss may occur as a result of damage to motoneurons in the spinal cord, focal delivery of E2 may reverse denervation and promote nerve sprouting in partially denervated muscle fibers. Preliminary studies suggest that a single administration of a combined fast-release (FNP-E2) and slow-release (SNP-E2) formulation to the contused spinal cord attenuates inflammatory cytokines/chemokines, gliosis, glial scarring, and neurogenic muscle loss. The focal delivery of E2 promotes microglial and astroglial differentiation to subpopulations of anti- inflammatory microglia/astrocytes which inhibit inflammation, axonal damage, and neuronal loss. Preliminary studies also suggest that NP-mediated delivery of E2 gel patch therapy reduces insult-induced muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx) proteins in vitro in myoblast cells and in vivo following mild to moderate SCI (40g/cm injury) in rats. However, whether NP-E2 gel patch therapy alters neuronal impairment and skeletal muscle loss in severe SCI (60g/cm injury) remains unknown. Thus, using a novel combined FNP- E2 and SNP-E2, may allow for suppression of acute inflammation by FNP-E2 and modulation of the inflammatory response by SNP-E2 thereafter. We hypothesize that focal delivery of combined FNP-E2 and SNP-E2 will minimize plasma E2 levels and increase local spinal cord concentrations - thereby reducing acute and subacute inflammation to promote recovery from neurogenic muscle loss in severe SCI. To test the hypothesis, three specific aims are proposed: (Aim 1) Determine the delivery of a combined FNP-E2 and SNP-E2 gel patch therapy and evaluate its kinetics, bio-distribution, toxicity, and effects in severe SCI model in rats; (Aim 2) Investigate the effects of a combined FNP-E2 and SNP-E2 therapy on neuronal impairment, glial scarring, and bladder/locomotor function in severe SCI; and (Aim 3) Examine the effects of a combined FNP-E2 and SNP- E2 therapy on skeletal muscle loss, neuroinflammation, and functional outcomes in severe SCI. Overall, the proposed combination strategy in a severe SCI model may provide insights into the mechanisms of estrogenic- driven neuroprotection and prevention of neurogenic muscle loss in severe SCI in combat veterans. Completion of this project should provide sufficient evidence to support the translation of E2 into clinical trials, with the ultimate goal of providing a safe and effective therapy to treat both veterans and the general population suffering from SCI.

严重脊髓损伤（SCI）是一种复杂的，使人衰弱的疾病，可导致永久性终身神经功能障碍。 赤字除了神经功能障碍外，SCI患者还因以下原因而经历神经源性肌肉损失： 不动神经功能缺损的改善和骨骼肌损失的预防与以下因素密切相关： SCI后功能恢复。导致神经元损伤和骨骼肌的分子机制 由于SCI造成的损失，仍然不完全理解。我们的实验室是最早证明类固醇 激素雌激素（E2）驱动的大鼠实验性SCI中的神经保护作用，表明E2值得临床应用 在神经创伤患者中进行评估。在SCI中发现10μg/kg E2的低剂量的有益作用， 但剂量保持在非生理剂量，用于人用，因此对临床使用造成安全性问题。 智能药物输送技术的出现，如纳米颗粒，可能会增加药物安全性 和改善的功效。因此，本提案的目标是检查新的快速和缓慢释放的效果 E2-负载的纳米颗粒（NP）对SCI大鼠挫伤模型中神经元功能障碍和骨骼肌损失的影响。 由于脊髓运动神经元损伤可能导致肌肉损失，因此E2的局部输送可能 逆转去神经支配并促进部分去神经肌肉纤维中的神经发芽。初步研究 表明组合快速释放（FNP-E2）和缓慢释放（SNP-E2）制剂单次给药 对挫伤的脊髓减弱炎性细胞因子/趋化因子、神经胶质增生、神经胶质瘢痕形成和神经源性 肌肉萎缩E2的局灶性递送促进小胶质细胞和星形胶质细胞分化为抗胶质细胞亚群。 炎性小胶质细胞/星形胶质细胞，其抑制炎症、轴突损伤和神经元损失。初步 研究还表明，NP介导的E2凝胶贴剂疗法的递送减少了由胰岛素诱导的肌肉RING， 在体外成肌细胞中和体内轻度 中度SCI（40 g/cm损伤）。然而，NP-E2凝胶贴剂治疗是否改变了神经元损伤， 严重SCI（60 g/cm损伤）的骨骼肌损失仍不清楚。因此，使用一种新的组合FNP- FNP-E2和SNP-E2可能允许通过FNP-E2抑制急性炎症和调节炎症性细胞因子。 SNP-E2的反应。我们假设联合FNP-E2和SNP-E2的局灶性给药将 最大限度地减少血浆E2水平，增加局部脊髓浓度-从而减少急性和亚急性 炎症，以促进严重SCI中神经源性肌肉损失的恢复。为了验证这个假设， 提出了具体目标：（目标1）确定组合的FNP-E2和SNP-E2凝胶贴剂的递送 治疗并评估其动力学，生物分布，毒性和在大鼠严重SCI模型中的作用;（目的2） 研究FNP-E2和SNP-E2联合治疗对神经元损伤、神经胶质瘢痕形成和 膀胱/运动功能在严重SCI;和（目的3）检查FNP-E2和SNP-1的组合的作用。 E2治疗对严重SCI患者骨骼肌损失、神经炎症和功能结局的影响总体看 在严重SCI模型中提出的联合策略可能会为雌激素机制提供见解， 驱动的神经保护和预防退伍军人严重SCI中的神经源性肌肉损失。完成 本项目的研究应提供足够的证据支持将E2转化为临床试验， 最终目标是提供一种安全有效的治疗方法来治疗退伍军人和普通人群的痛苦 SCI的。

项目成果

Current Studies of Immunotherapy on Glioblastoma

• DOI: 10.19104/jnn.2014.104
• 发表时间: 2014-04
• 期刊: Journal of neurology and neurosurgery
• 作者: Neena S. Agrawal;Rickey Miller;R. Lal;Harshini Mahanti;Yaenette N. Dixon-Mah;Michele L Decandio;W. Alex;Vandergrift Iii;A. Varma;Sunil J. Patel;N. Banik;S. Lindhorst;P. Giglio;Arabinda Das;Ralph H Johnson

MiR-7-1 potentiated estrogen receptor agonists for functional neuroprotection in VSC4.1 motoneurons.

• DOI: 10.1016/j.neuroscience.2013.10.027
• 发表时间: 2014-01-03
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Chakrabarti M;Banik NL;Ray SK
• 通讯作者: Ray SK

Mechanisms and clinical significance of histone deacetylase inhibitors: epigenetic glioblastoma therapy.

• 发表时间: 2015-02
• 期刊: Anticancer research
• 影响因子: 2
• 作者: Philip Lee;Ben Murphy;Rickey Miller;Vivek D. Menon;N. Banik;P. Giglio;S. Lindhorst;A. Varma;W. Vandergrift;Sunil J. Patel;Arabinda Das

Molecular Targets and Treatment of Meningioma.

脑膜瘤的分子靶点和治疗。

• 发表时间: 2014
• 期刊: Journal of neurology and neurosurgery
• 作者: MillerJr,Rickey;DeCandio,MicheleL;Dixon-Mah,Yaenette;Giglio,Pierre;Vandergrift3rd,WAlex;Banik,NarenL;Patel,SunilJ;Varma,AbhayK;Das,Arabinda
• 通讯作者: Das,Arabinda

Calpain activation and progression of inflammatory cycles in Parkinson's disease.

• DOI: 10.31083/j.fbl2701020
• 发表时间: 2022-01-13
• 期刊: FRONTIERS IN BIOSCIENCE-LANDMARK
• 影响因子: 3.1
• 作者: Gao, Andrew;McCoy, Hannah M.;Zaman, Vandana;Shields, Donald C.;Banik, Naren L.;Haque, Azizul
• 通讯作者: Haque, Azizul