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，会导致运动缺陷、疼痛和认知障碍 恶化。调查军事人员自身免疫性疾病的研究表明， 退伍军人中的多发性硬化症，强调了对退伍军人进行新疗法研究的重要性 受该疾病的影响尤为严重。目前的多发性硬化症药物是非治愈性的，需要终身治疗 以减缓残疾的进展。此外，许多治疗方案都具有广泛的免疫抑制作用 易受危及生命的感染的患者。多发性硬化症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，保持健康的免疫力完好无损。 当淋巴细胞（例如 TH17 和 TH1 T 细胞）攻击中枢神经系统中的髓磷脂，从而导致 MS 发生时， 导致神经退行性变。细胞代谢正在成为一种高度相关的干扰治疗工具 免疫细胞亚群的活性。令人感兴趣的是三羧酸（TCA）循环的中间体，已证明 富马酸二甲酯（(DMF)，Tecfidera）成功治疗复发缓解型多发性硬化症。然而，患者 每天服用 DMF 会增加免疫抑制的风险，从而导致潜在的致命 病毒感染引起的并发症。衣康酸衍生自 TCA 循环中间体，并已被证明可以 抑制白细胞介素 6 (IL-6) 的产生，而不影响其他细胞因子，例如肿瘤坏死因子 a (TNFa)，在增强免疫反应中发挥重要作用。 IL-6 由树突状细胞 (DC) 分泌 巨噬细胞以调节性 T 细胞 (TREG) 为代价促进炎症 TH17 T 细胞的分化 其功能是抑制自身免疫活动。初步研究表明衣康酸可以保护小鼠免受 实验性自身免疫性脑脊髓炎（EAE），MS 的临床前啮齿动物模型。在充满希望的同时，这些 效果需要每日、大剂量治疗。聚合物颗粒形式的生物材料具有以下特性： 细胞靶向和控释可提高治疗效果、特异性并减少频繁治疗的需要 剂量。因此，该提案的中心假设是 DC 和粒子能够以粒子方式摄取衣康酸 巨噬细胞会减少 IL-6 的产生，并将致病性炎症 T 细胞反应转变为调节性反应 表型，提供针对 EAE 的保护。我将通过三个具体目标来检验这个假设：1）设计 并验证粒子合成和吸收； 2) 确定聚合物颗粒中衣康酸的影响 对免疫细胞代谢和功能的影响； 3）确认和定义体内功效的机制和 EAE 的特异性。因此，VA 对职业发展奖 (CDA-2) 的支持将有助于开发 将生物材料与免疫调节代谢物相结合的新策略，可能提供更有效、 针对患有多发性硬化症的退伍军人的特殊治疗。 这项拟议的研究是职业和指导计划的一部分，该计划将使我的发展成为共同的目标 被任命为 VA 科学家和学术机构的教员，领导 VA 资助的项目。一个辅导 团队由 VA 研究人员和临床科学家组成，他们在免疫工程、代谢、 MS Veteran 的护理将在培训领域提供指导，以提高我的概念和技术掌握能力 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技能的发展。这些目标 得到我过去在研究免疫介导疾病方面的培训和生产力的支持，并将推出我的 进入退伍军人管理局进行有影响力的研究，解决影响退伍军人的多发性硬化症和自身免疫性疾病。 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 R01 奖项，2) 建立了强大的 VA 联系，以核心互补的研究方向。 总之，这将使我准备好领导一个基于生物材料的独立、全面的研究项目 提供代谢物，使患有多发性硬化症等自身免疫性疾病的退伍军人受益。