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.

当前的研究活动集中于脊髓损伤（SCI），帕金森氏病（PD）和多个 硬化症（MS）。 SCI是一种复杂的衰弱状况 损失和肌肉萎缩由于不动。我们的实验室是最早表明雌激素（E2）驱动器的实验室之一 大鼠实验性SCI的神经保护作用，表明E2保证神经瘤中的临床评估。新的 包括纳米颗粒在内的智能药物输送技术可能可以提高药物安全性并改善 效力。这是目的是检查新型缓慢释放E2负载的纳米颗粒（SNP-E2）凝胶的影响 SCI大鼠模型中神经元功能障碍和骨骼肌损失的补丁。我们假设焦点交付 通过缓慢释放纳米颗粒SNP-E2的雌激素将保持低的全身E2水平（等离子体）和较高 组织浓度，从而允许从神经和骨骼中恢复最大的热潜力 科学肌肉损失。为了检验假设，提出了两个具体目标：（目标1）检查 新型缓慢释放SNP-E2并确定其动力学，生物分布，毒性以及现代和影响的影响 严重的SCI和（AIM 2）确定SNP-E2对中等和中等骨骼肌肉损失改变的影响 严重的科学。总体而言，拟议的研究应为改善健康和 具有SCI的退伍军人的功能恢复。 帕金森氏病（PD）是一种影响近80,000名退伍军人的进行性退行性疾病。尽管 这种退化过程的机制仍然难以捉摸，可能涉及慢性炎症。钙蛋白酶 不仅在大脑（SN-DA神经元）和脊髓（SC）变性中起关键作用 炎症和疾病进展。抑制钙蛋白 MPTP小鼠，表明Calpain参与炎症过程。我们的目标是开发治疗 用阻断炎症过程，保护神经元，控制疾病的药物治疗PD的策略 进展并提高功能。我们假设钙蛋白酶激活，炎性T细胞的浸润 （TH1/TH17），并且释放的细胞因子和趋化因子参与PD的进行性变性和钙蛋白酶 抑制剂治疗可以减少变性，疾病进展缓慢并改善功能。两个具体的目标 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 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 血清，并确定SC中的细胞死亡参数和钙蛋白酶激活； （目标2）检查是否处理 使用钙蛋白酶抑制剂的MPTP小鼠将减少退化性炎症事件并改善功能。 在MS及其动物模型中也发现了钙蛋白酶活性的增加[实验自身免疫性 T细胞的激活（TH1/TH17），轴突/髓磷脂的降解和疾病（EAE）]和钙蛋白酶表示。 T细胞趋化性。虽然Calpain在MS患者的大脑和脊髓中被激活，但 两种钙蛋白酶同工型calpain-1和calpain-2仍然不确定。我们假设激活不同 Calpain同工型可能有利于MS患者的炎症介质和Th1/Th17细胞的扩展，这可能 被钙蛋白酶抑制减弱。研究包括（目标1）测试MS患者样本以确定哪个 两种主要的钙蛋白酶亚型参与免疫细胞类型的失调，影响 疾病; （AIM 2）研究一种独特的钙蛋白酶同工型是否与疾病进展，影响 - 在MS中加密神经退行性过程。获得的数据将揭示钙蛋白酶抑制剂对抑制作用的影响 疾病发育的特定钙和免疫和神经退行性臂的衰减 用于治疗MS和其他神经退行性疾病的新型疗法。这些研究项目的总体目标 是为了最大程度地减少变性，最大化功能并改善退伍军人的健康状况。