Research Career Scientist for Naren Banik, PhD

Naren Banik 博士的研究职业科学家

• 批准号: 10476736
• 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: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10476736
• 关键词: Affect; Animal Diseases; Animal Model; Attenuated; Autoimmune Diseases; Axon; Biochemical; Biodistribution; Bladder; Bone Density; Brain; Calpain; Cell Death; Cells; Chemotaxis; Chronic; Clinical; Complex; Data; Degenerative Disorder; Disease; Disease Progression; Doctor of Philosophy; Dose; Drug Delivery Systems; Estrogens; Event; F-Box Proteins; Gel; Goals; Health; Immune; Impairment; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Injury; Investigation; Kinetics; Laboratories; Lesion; Life; Link; MPTP mouse; MPTP treatment; Medical; Methylprednisolone; Microglia; Modeling; Multiple Sclerosis; Muscle Fibers; Muscular Atrophy; Myelin; Myoblasts; Nerve Degeneration; Nervous System Trauma; Neurodegenerative Disorders; Neurologic Deficit; Neuronal Dysfunction; Neuronal Injury; Neurons; Neurophysiology - biologic function; Parkinson Disease; Pathway interactions; Plasma; Play; Process; Property; Protein Isoforms; Rattus; Recovery; Recovery of Function; Regulation; Research; Research Activity; Research Project Grants; Role; Safety; Sampling; Scientist; Site; Skeletal Muscle; South Carolina; Spinal Cord; Spinal Injuries; Spinal cord injury; Substantia nigra structure; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Tumor-infiltrating immune cells; Universities; Veterans; arm; attenuation; bone loss; calpain inhibitor; career; cell motility; cell type; chemokine; cytokine; disorder control; dopaminergic neuron; improved; improved functioning; in vivo; medication safety; motor impairment; multiple sclerosis patient; muscle RING finger 1; muscle degeneration; myelin degeneration; nanoparticle; neuroprotection; novel; novel strategies; novel therapeutics; preservation; programs; relating to nervous system; research clinical testing; skeletal muscle wasting; translational potential

Current research activities are focused on Spinal Cord Injury (SCI), Parkinson’s Disease (PD), and Multiple Sclerosis (MS). SCI is a complex debilitating condition leading to life-long neurological deficits as well as bone loss and muscle atrophy due to immobility. Our laboratory was among the first to show that estrogen (E2) drives neuroprotection in experimental SCI in rats, suggesting E2 warrants clinical evaluation in neurotrauma. New smart drug delivery techniques, including nanoparticles, may allow for increased drug safety and improved efficacy. Thus, the goal is to examine the effects of a novel slow release E2-loaded nanoparticle (SNP-E2) gel patch on neuronal dysfunction and skeletal muscle loss in a rat model of SCI. We hypothesize that focal delivery of estrogen via slow release nanoparticles SNP-E2 will maintain low systemic E2 levels (plasma) and higher tissue concentrations, thereby allowing for maximized therapeutic potential for recovery from neural and skeletal muscle loss in SCI. To test the hypothesis, two specific aims are proposed: (Aim 1) Examine the delivery of a novel slow release SNP-E2 and determine its kinetics, bio-distribution, toxicity, and effects in moderate and severe SCI and (Aim 2) Determine the effects of SNP-E2 on alterations of skeletal muscle loss in moderate and severe SCI. Overall, the proposed studies should provide a safe and novel strategy to improve health and functional recovery for Veterans with SCI. Parkinson’s disease (PD) is a progressive degenerative disorder affecting almost 80,000 Veterans. While the mechanisms of this degenerative process remain elusive, chronic inflammation may be involved. Calpain not only plays a pivotal role in brain (SN-DA neurons) and spinal cord (SC) degeneration, it may also drive inflammation and disease progression. Inhibition of calpain attenuates a distinct subpopulation of T cells in MPTP mice, suggesting calpain’s involvement in the inflammatory process. Our goal is to develop therapeutic strategies to treat PD with agents that block the inflammatory process, protect neurons, control disease progression, and improve function. We hypothesize that calpain activation, infiltration of inflammatory T cells (Th1/Th17), and released cytokines and chemokines are involved in progressive degeneration of PD, and calpain inhibitor treatment may reduce degeneration, slow disease progression, and improve function. Two specific aims will test the hypothesis: (Aim 1) Investigate the role of calpain regulation and T cell infiltration in SC degeneration and disease progression in MPTP mice, characterize infiltrating T cells, assess cytokine/chemokine levels in sera, and determine cell death parameters and calpain activation in SC; (Aim 2) Examine whether treatment of MPTP mice with calpain inhibitor will reduce degenerative inflammatory events and improve function. Increased calpain activity has also been found in MS as well as in its animal model [experimental autoimmune disease (EAE)], and calpain is implicated in the activation of T cells (Th1/Th17), degradation of axon/myelin, and T cell chemotaxis. While calpain is activated in brain and spinal cord of MS patients, the precise involvement of the two calpain isoforms, calpain-1 and calpain-2, remains undefined. We hypothesize that activation of distinct calpain isoform may favor expansion of inflammatory mediators and Th1/Th17 cells in MS patients, which could be attenuated by calpain inhibition. Studies include (Aim 1) testing MS patient samples to determine which of the two major calpain isoforms is involved in dysregulation of immune cell types, influencing immune arms of the disease; and (Aim 2) Investigating whether a distinct calpain isoform is linked with disease progression, influ- encing the neurodegenerative process in MS. Data obtained will reveal the effect of calpain inhibitor on inhibition of specific calpains and attenuation of both immune and neurodegenerative arms of the disease for developing novel therapy for treating MS and other neurodegenerative diseases. The overall goal of these research projects is to minimize degeneration and maximize function and improve the health of our Veterans.

目前的研究活动集中在脊髓损伤 (SCI)、帕金森病 (PD) 和多发性硬化症 硬化症 (MS) 是一种复杂的衰弱性疾病，会导致终生神经功能缺损和骨骼损伤。 我们的实验室是最早证明雌激素 (E2) 驱动的实验室之一。 大鼠实验性 SCI 中的神经保护作用，表明 E2 值得在神经创伤中进行临床评估。 包括纳米粒子在内的智能药物输送技术可以提高药物安全性并改善 因此，我们的目标是检查新型缓释 E2 负载纳米颗粒 (SNP-E2) 凝胶的效果。 我们与 SCI 大鼠模型中的神经元功能障碍和骨骼肌损失进行了斗争。 通过缓释纳米颗粒 SNP-E2 释放雌激素将维持较低的全身 E2 水平（血浆）和较高水平 组织浓度，从而最大限度地发挥神经和骨骼恢复的治疗潜力 为了检验 SCI 中的肌肉损失，提出了两个具体目标：（目标 1）检查 SCI 中肌肉损失的情况。 新型缓释 SNP-E2 并确定其动力学、生物分布、毒性和中度和中度作用 严重 SCI 和（目标 2）确定 SNP-E2 对中度和 总体而言，拟议的研究应提供一种安全且新颖的策略来改善健康和 患有 SCI 的退伍军人的功能恢复。 帕金森病 (PD) 是一种进行性退行性疾病，影响着近 80,000 名退伍军人。 这种退化过程的机制仍然难以捉摸，可能涉及钙蛋白酶。 它不仅在大脑（SN-DA 神经元）和脊髓（SC）变性中发挥关键作用，还可能驱动 炎症和疾病进展中钙蛋白酶的抑制会削弱 T 细胞的独特亚群。 MPTP 小鼠，表明钙蛋白酶参与炎症过程。我们的目标是开发治疗方法。 使用阻断炎症过程、保护神经元、控制疾病的药物治疗帕金森病的策略 我们进展了钙蛋白酶激活、炎症 T 细胞浸润。 (Th1/Th17)，释放的细胞因子和趋化因子参与 PD 和钙蛋白酶的进行性退化 抑制剂治疗可以减少变性、减缓疾病进展和改善功能。 将检验假设：（目标 1）研究钙蛋白酶调节和 T 细胞浸润在 SC 变性中的作用 和 MPTP 小鼠的疾病进展，表征浸润 T 细胞，评估细胞因子/趋化因子水平 （目标 2）检查是否治疗 使用钙蛋白酶抑制剂的 MPTP 小鼠将减少退行性炎症事件并改善功能。 在多发性硬化症及其动物模型中也发现钙蛋白酶活性增加[实验性自身免疫] 疾病 (EAE)]，钙蛋白酶与 T 细胞 (Th1/Th17) 的激活、轴突/髓磷脂的降解以及 当多发性硬化症患者的大脑和脊髓中钙蛋白酶被激活时，T细胞趋化性的精确参与。 两种钙蛋白酶异构体 calpain-1 和 calpain-2 仍未定义。 钙蛋白酶亚型可能有利于多发性硬化症患者炎症介质和 Th1/Th17 细胞的扩增，这可能 研究包括（目标 1）测试 MS 患者样本以确定哪些。 两种主要的钙蛋白酶异构体参与免疫细胞类型的失调，影响免疫细胞的免疫臂 （目标 2）研究一种独特的钙蛋白酶亚型是否与疾病进展、流感- 所获得的数据将揭示钙蛋白酶抑制剂的抑制作用。 特定钙蛋白酶的作用以及该疾病的免疫和神经退行性疾病的减弱 这些研究项目的总体目标是治疗多发性硬化症和其他神经退行性疾病的新疗法。 是最大限度地减少退化并最大限度地提高功能并改善退伍军人的健康。