Biomaterials-Enabled Delivery of Immunometabolic Modulators to Improve Treatment Options for Multiple Sclerosis in Veterans

生物材料支持免疫代谢调节剂的传递，以改善退伍军人多发性硬化症的治疗选择

• 批准号: 10485326
• 负责人: SENTA KAPNICK
• 金额: --
• 依托单位: BALTIMORE VA 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: 2023-09-30 至 2028-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485326
• 关键词: Affect; Antigens; Area; Autoimmune; Autoimmune Diseases; Award; Biocompatible Materials; Biological Assay; Biomedical Engineering; Body Weight decreased; Caring; Cell Differentiation process; Cell Separation; Cell physiology; Cells; Cellular Metabolic Process; Central Nervous System; Cerebrospinal Fluid; Citric Acid Cycle; Clinical; Cognitive; Complication; Data; Dendritic Cells; Deterioration; Development; Disease; Dose; Environment; Experimental Autoimmune Encephalomyelitis; Faculty; Flow Cytometry; Frequencies; Fumarates; Funding; Genetic Transcription; Genomics; Goals; Growth; Human; Image; Immune; Immune response; Immunity; Immunocompromised Host; Immunosuppression; Incidence; Infection; Inflammation; Inflammatory; Injections; Institution; Interleukin-6; K-Series Research Career Programs; Lead; Leadership; Lesion; Libraries; Life; Lymphocyte; Macrophage; Measures; Mediating; Mentors; Metabolic Pathway; Metabolism; Microscopy; Military Personnel; Mitochondria; Mononuclear; Motor; Multiple Sclerosis; Mus; Myelin; Nerve Degeneration; Oral; Pain; Paralysed; Pathogenicity; Pathologic; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Play; Polymers; Predisposition; Production; Productivity; Progressive Multifocal Leukoencephalopathy; Property; Publishing; Quality of life; Refractory; Regulation; Regulatory T-Lymphocyte; Relapsing-Remitting Multiple Sclerosis; Research; Research Personnel; Risk; Rodent Model; Role; Scientist; Sensory; Signal Transduction; Source; Specificity; Spectrum Analysis; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Therapeutic; Training; Treatment Efficacy; United States National Institutes of Health; Vaccination; Veterans; Virus Diseases; Woman; Work; career; career development; cellular targeting; compliance behavior; controlled release; cytokine; design; disability; factor A; immune function; immunoengineering; immunoregulation; improved; in vivo; insight; interest; light scattering; lymph nodes; materials science; member; metabolomics; motor deficit; mouse model; multiple sclerosis patient; multiple sclerosis treatment; myelination; novel strategies; novel therapeutics; particle; polarized cell; pre-clinical; programs; restraint; risk variant; skills; success; tool; translational potential; uptake

Multiple sclerosis (MS) is an inflammatory, autoimmune disease resulting in motor deficits, pain, and cognitive deterioration. Studies investigating autoimmune disorders in military personnel have shown higher incidence of MS among Veterans, highlighting the importance of research in novel therapeutics for Veterans that are disproportionately impacted by the disease. Current MS drugs are non-curative and require life-long treatment to slow progression of disability. In addition, many treatment options are broadly immunosuppressive leaving patients susceptible to life-threatening infections. New strategies for MS treatment should increase efficacy, require fewer doses, and control specific aspects of pathological inflammation, leaving healthy immunity intact. MS occurs when lymphocytes (e.g., TH17 and TH1 T cells), attack myelin in the central nervous system that leads to neurodegeneration. Cell metabolism is emerging as a highly relevant therapeutic tool for interfering with activities of immune cell subsets. Of interest are intermediates of the tricarboxylic acid (TCA) cycle, demonstrated by the success of dimethyl fumarate ((DMF), Tecfidera) for treating relapsing-remitting MS. However, patients prescribed daily, oral DMF are at increased risk of immunosuppression that leads to potentially lethal complications from viral infection. Itaconate is derived from a TCA cycle intermediate and has been shown to suppress production of Interleukin-6 (IL-6), without impacting other cytokines, such as tumor necrosis factor a (TNFa), that play an important role in mounting immune responses. IL-6 secreted by dendritic cells (DCs) and macrophages promotes differentiation of inflammatory TH17 T cells at the expense of regulatory T cells (TREG) whose function is to suppress autoimmune activity. Preliminary studies indicate that itaconate protects mice from experimental autoimmune encephalomyelitis (EAE), the preclinical rodent model of MS. While promising, these effects required daily, high dose treatments. Biomaterials in the form of polymer particles offer features such as cell targeting and controlled release that improve treatment efficacy, specificity, and reduce the need for frequent dosing. Thus, the central hypothesis of this proposal is that particle-enabled uptake of itaconate by DCs and macrophages will reduce IL-6 production and shift the pathogenic inflammatory T cell response to a regulatory phenotype, providing protection against EAE. I will test this hypothesis through three specific aims: 1) design and validate particle synthesis and uptake; 2) determine the impact of itaconate packaged in polymer particles on immune cell metabolism and function; and 3) confirm and define the mechanisms of in vivo efficacy and specificity in EAE. Thus, VA support for this Career Development Award (CDA-2) will enable development of a novel strategy combining biomaterials with immunomodulatory metabolites that potentially offers more effective, specific treatments for Veterans with MS. This proposed research is part of a career and mentoring plan that will nucleate my development into a jointly appointed VA scientist and faculty member at an academic institution leading VA-funded projects. A mentoring team composed of VA researchers and clinician scientists with expertise in immune engineering, metabolism, and MS Veteran’s care will provide guidance in training areas to develop my conceptual and technical mastery of materials science, integration with the VA and its Veterans, and growth of my leadership skills. These goals are supported by my past training and productivity in studying immune-mediated diseases and will launch my entry into the VA conducting impactful research that tackles MS and autoimmune disorders affecting Veterans. Upon completion of this CDA-2, I will have 1) published high impact work facilitating my application for VA Merit and NIH R01 awards, and 2) established strong VA connections to nucleate complementary research directions. Together, this will prepare me to lead an independent, holistic research program built on the biomaterials-based delivery of metabolites that will benefit Veterans with autoimmune disorders such as MS.

多发性硬化症（MS）是一种炎症性自身免疫性疾病，导致运动缺陷、疼痛和认知功能障碍。 恶化调查军事人员自身免疫性疾病的研究显示， 退伍军人中的MS，强调研究新疗法对退伍军人的重要性， 不成比例地受到疾病的影响。目前的MS药物是非治愈性的，需要终身治疗 来减缓残疾的发展。此外，许多治疗选择广泛免疫抑制离开 易受危及生命的感染的患者。MS治疗的新策略应该会提高疗效， 需要更少的剂量，并控制病理性炎症的特定方面，使健康的免疫力完好无损。 当淋巴细胞（例如，TH 17和TH 1 T细胞），攻击中枢神经系统中的髓鞘， 导致神经退化细胞代谢正在成为一种高度相关的治疗工具， 免疫细胞亚群的活性。感兴趣的是三羧酸（TCA）循环的中间体， 富马酸二甲酯（（DMF），Tecfidera）成功治疗复发缓解型MS。然而， 每日处方，口服DMF的免疫抑制风险增加， 病毒感染的并发症。衣康酸衍生自TCA循环中间体，并且已显示出 抑制白细胞介素-6（IL-6）的产生，而不影响其他细胞因子，如肿瘤坏死因子a （TNFa），其在增加免疫应答中起重要作用。由树突状细胞（DC）分泌的IL-6和 巨噬细胞以调节性T细胞（Treg）为代价促进炎性TH 17 T细胞的分化 其功能是抑制自身免疫活性。初步研究表明，衣康酸可保护小鼠免受 实验性自身免疫性脑脊髓炎（EAE），MS的临床前啮齿动物模型。 需要每天进行高剂量治疗。聚合物颗粒形式的生物材料具有以下特点， 细胞靶向和控制释放，提高治疗效果，特异性，并减少需要频繁 剂量。因此，这一建议的中心假设是，颗粒使能的DC摄取衣康酸， 巨噬细胞将减少IL-6的产生，并将致病性炎性T细胞反应转变为调节性T细胞反应。 表型，提供针对EAE的保护。我将通过三个具体目标来检验这一假设：1）设计 并验证颗粒合成和摄取; 2）确定包装在聚合物颗粒中的衣康酸盐的影响 对免疫细胞代谢和功能的影响;以及3）确认和定义体内功效的机制， EAE的特异性。因此，退伍军人事务部对职业发展奖（CDA-2）的支持将使 将生物材料与免疫调节代谢物相结合的新策略， 为退伍军人提供特殊治疗。 这项拟议的研究是职业生涯和指导计划的一部分，将使我的发展成为一个共同的 被任命为VA科学家和教员在一个学术机构领导VA资助的项目。一个辅导 由VA研究人员和临床科学家组成的团队，具有免疫工程，代谢， 和MS退伍军人的照顾将提供指导，在培训领域，以发展我的概念和技术掌握 材料科学，与退伍军人管理局及其退伍军人的融合，以及我的领导能力的增长。这些目标 我过去在研究免疫介导疾病方面的培训和生产力支持了我，并将推出我的 进入VA进行有影响力的研究，解决MS和影响退伍军人的自身免疫性疾病。 完成CDA-2后，我将1）发表高影响力的作品，以促进我申请VA Merit 和NIH R 01奖，2）建立了强大的VA连接，以核互补的研究方向。 总之，这将使我准备领导一个独立的，全面的研究计划，建立在生物材料的基础上， 代谢物的传递，这将有利于退伍军人与自身免疫性疾病，如MS。