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

多发性硬化症(MS)是一种炎症性自身免疫性疾病，导致运动障碍、疼痛和认知 恶化。调查军事人员自身免疫性疾病的研究表明， MS在退伍军人中的应用，强调了对退伍军人进行新疗法研究的重要性 不成比例地受到这种疾病的影响。目前的多发性硬化症药物无法治愈，需要终生治疗。 以减缓残疾的进展。此外，许多治疗选择都是广泛的免疫抑制离开。 容易受到危及生命的感染的患者。治疗多发性硬化症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，保持健康的免疫力不变。 当淋巴细胞(如TH17和TH1T细胞)攻击中枢神经系统中的髓鞘时，就会发生MS 会导致神经退化。细胞新陈代谢正在成为一种高度相关的治疗工具，用于干扰 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，证明了 富马酸二甲酯(DMF，Tecfidera)治疗复发缓解型多发性硬化症的成功，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。依他康酸酯是从TCA环中间体中衍生出来的，已被证明 抑制白介素6(IL-6)的产生，不影响其他细胞因子，如肿瘤坏死因子a (TNFa)，在增强免疫反应方面发挥重要作用。树突状细胞(DC)分泌IL-6和 巨噬细胞促进炎性TH17 T细胞分化，损害调节性T细胞(Treg) 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)是MS的临床前啮齿动物模型，虽然前景看好，但这些 每天都需要大剂量的治疗。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，提高了治疗效果和特异性，并减少了频繁 给药。因此，这一提议的中心假设是DC和DCs对衣康酸的微粒摄取 巨噬细胞会减少IL-6的产生，并将致病性炎性T细胞的反应转移到调节性 表型，提供对EAE的保护。我将通过三个具体目标来检验这一假设：1)设计 并验证颗粒的合成和摄取；2)确定聚合物颗粒中包装的衣康酸的影响 对免疫细胞代谢和功能的影响；3)确认和确定体内疗效和功能的机制 EAE的特异性。因此，退伍军人管理局对这一职业发展奖(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，可能提供更有效的， 退伍军人多发性硬化症的具体治疗 这项拟议的研究是职业生涯和指导计划的一部分，它将使我的发展成为共同的 被任命为退伍军人管理局科学家和教员，领导退伍军人管理局资助的项目。一次辅导 团队由退伍军人管理局研究人员和临床科学家组成，他们在免疫工程、新陈代谢、 微软老兵的关怀将在培训领域提供指导，以发展我的概念和技术掌握 材料科学，与退伍军人和退伍军人的融合，以及我领导技能的增长。这些目标 得到了我过去在研究免疫介导性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。 完成这项CDA-2后，我将有1)出版的高影响力的工作，以促进我的退伍军人管理局荣誉申请 和NIH R01奖项，以及2)建立了强大的VA联系，以形成互补的研究方向。 总之，这将为我领导一个独立的、全面的研究项目做好准备，该项目建立在基于生物材料的 代谢物的输送将使患有自身免疫性疾病的退伍军人受益，如MS。

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.