BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10454215
• 负责人: ARTHUR A. VANDENBARK
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454215
• 关键词: Acute; Address; Affect; Alcohol abuse; Antigen-Presenting Cells; Autoimmune; Autoimmunity; Award; Binding; Biological; Blood; Cells; Chronic; Clinical Research; Clinical Trials; Degenerative Disorder; Demyelinations; Development; Disease; Dopachrome isomerase; Dose; Early treatment; Estrogen Receptors; Evaluation; Experimental Autoimmune Encephalomyelitis; Female; Generations; Genotype; Grant; HLA-DR2 Antigen; Histocompatibility Antigens Class II; Histocompatibility Testing; Homologous Gene; Human; Inflammation; Inflammatory; Injury; Laboratories; Ligands; Link; MHC Class II Genes; Methamphetamine; Migration Inhibitory Factor; Mission; Molecular Chaperones; Molecular Conformation; Multiple Sclerosis; Mus; Nerve Degeneration; Neuraxis; Peptides; Post-Traumatic Stress Disorders; Process; Progressive Disease; Property; Publishing; Research; Risk; Risk Factors; Scientist; Sequence Homologs; Services; Signal Transduction; Stroke; Substance abuse problem; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Tissues; Traumatic Brain Injury; Vascular Dementia; Veterans; Work; antagonist; career; chronic neurologic disease; cognitive disability; cytokine; design; immunoregulation; interest; male; molecular modeling; mouse model; neuroimmunology; neuroprotection; new therapeutic target; novel; novel therapeutic intervention; oligodendrocyte-myelin glycoprotein; phase 1 study; preclinical study; prevent; programs; receptor; recruit; treatment effect

The mission of my Neuroimmunology Research Program is to develop a deep biological understanding of autoimmune, demyelinating and neurodegenerative processes that affect the central nervous system (CNS) and to identify and test novel disease-relevant therapies that can be brought to market to treat and/or cure these conditions. Veterans are currently developing intractable chronic neurological diseases such as multiple sclerosis (MS) and stroke, service related injuries including traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD), and substance abuse of alcohol and methamphetamine. Studies carried out by our laboratory are highly relevant to these devastating conditions due to our development of a novel therapy that targets a common underlying mechanism, the MIF/CD74 axis that promotes chronic inflammation in the CNS and other tissues. MIF (macrophage migration inhibitory factor) and its homolog D-DT (D-dopachrome tautomerase) are highly inflammatory cytokines that trigger release of other inflammatory factors upon binding and signaling through their common receptor, CD74, a chaperone for loading self and foreign peptides into MHC class II molecules on antigen presenting cells (APC). The result of MIF/CD74 signaling is peptide-specific Teffector cell activation and recruitment of inflammatory cells from blood into the CNS. Our initial unique therapeutic construct, called RTL1000 is comprised of linked DRα1 and DRβ1 domains of HLA-DR2 (an MS risk factor) covalently linked to myelin oligodendrocyte glycoprotein (MOG) 35-55. This construct has conformational similarity to naturally occurring MHC class II/peptide T cell receptor ligands, but induces T cell tolerance when present in soluble form without cell-bound co-stimulatory molecules on APC. This construct has immunoregulatory and neuroprotective properties in a mouse model of MS (experimental autoimmune encephalomyelitis, EAE) and was shown to be safe and well tolerated in a Phase 1 study in MS. RTL1000 will soon be tested in a multi-dose MS clinical trial. The major breakthrough in understanding the potent effects of RTL1000 occurred in 2013 with the discovery of CD74 as the cellular receptor for RTL1000. This led to the unifying discovery that RTL1000 could competitively inhibit binding of both MIF and D-DT to CD74 and thus short-circuit MIF/CD74 signaling that is present in essentially all of the VA targeted CNS conditions. Molecular modeling of MIF binding revealed two discrete CD74 regions that bound to homologous sequences on MIF and D-DT and to the DRα1 moiety of RTL1000, thus explaining RTL1000’s competitive inhibition. However, RTL1000 can only be used in ~60% of MS subjects that express HLA-DR2. We thus designed a new construct, DRα1-MOG-35-55 that retained the activities of RTL1000 and could modulate CD74 and competitively block MIF binding, resulting in a significant treatment effect and neuroprotection in chronic EAE. Of interest, RTL1000 and DRα1-MOG-35-55 were more effective in treating chronic EAE in male mice due to an antagonist effect of estrogen receptor (ESR1) in females. An evaluation of MIF, D-DT and CD74 in a ~600 subject clinical study (to be published in PNAS) revealed that male subjects with a high expression genotype for MIF (and D-DT) had an increased risk of developing progressive MS. This unique observation raises the possibility that early treatment of males with RTL1000 or DRα1-MOG-35-55 might prevent conversion to progressive MS and potentially would be effective for treating MS subjects with progressive disease. FDA IND approval of DRα1-MOG-35-55 preclinical studies would allow treatment of all MS subjects regardless of the HLA type due to its non-polymorphic, universal expression that would be tolerated by all humans and thus could be injected without tissue typing. Of broader importance, we have demonstrated that RTL1000 and DRα1-MOG-35-55 constructs can also treat other CNS conditions in experimental mouse models including experimental stroke, vascular dementia, traumatic brain injury and methamphetamine induced cognitive disability, thus providing a novel potential therapy for Veterans that develop these devastating conditions.

我的神经免疫学研究计划的使命是对 影响中枢神经系统（CNS）的自身免疫，脱髓鞘和神经退行性过程 并识别和测试可将疾病与疾病相关的新型疗法，这些疗法可将其推向市场以治疗和/或治愈 这些条件。退伍军人目前正在发展棘手的慢性神经系统疾病，例如多种 硬化症（MS）和中风，与服务相关的伤害，包括创伤性脑损伤（TBI）和创伤后 应激障碍（PTSD）以及酒精和甲基​​苯丙胺的药物滥用。我们进行的研究 由于我们开发了一种新型疗法，实验室与这些破坏性疾病高度相关 靶向常见的基本机制，即促进CNS慢性炎症的MIF/CD74轴 和其他组织。 MIF（巨噬细胞迁移抑制因子）及其同源DT（D-DOPACHROME 互变异酶）是高度炎性细胞因子，在结合后触发其他炎症因子的释放 并通过其公共接收器CD74发出信号，这是一种将自我和外肽加载到的伴侣 MHC II类分子在抗原呈递细胞上（APC）。 MIF/CD74信号的结果是辣椒特异性的 从血液进入中枢神经系统的炎性细胞激活和募集。我们最初的独特 HLA-DR2的链接DRα1和DRβ1结构域包括称为RTL1000的治疗构建体（MS 风险因素）共价与髓磷脂少突胶质细胞糖蛋白（MOG）35-55相关。这个结构有 与自然发生的MHC II/肽T细胞接收器配体的构象相似性，但诱导T细胞 耐受性在APC上以固体形式存在而没有细胞结合的共刺激分子。这个结构 在MS的小鼠模型中具有免疫调节和神经保护特性（实验自身免疫） 脑脊髓炎，EAE），在MS中的1期研究中被证明是安全且耐受性的。 RTL1000 Will 很快在多剂量MS临床试验中进行测试。理解的主要突破是理解的潜在影响 RTL1000发生在2013年，发现CD74是RTL1000的蜂窝接收器。这导致了 统一发现RTL1000可以竞争地抑制MIF和D-DT与CD74的结合，从而 在本质上所有的VA靶向中枢神经系统条件中呈现的短路MIF/CD74信号传导。分子 MIF结合的建模揭示了两个离散的CD74区域，这些区域与MIF和MIF上的同源序列结合 D-DT和RTL1000的DRα1部分，从而解释了RTL1000的竞争性抑制作用。然而， RTL1000只能在表达HLA-DR2的MS受试者的约60％中使用。因此，我们设计了一个新的 构造，DRα1-MOG-35-55保留了RTL1000的活性，可以调节CD74和 竞争性阻断MIF结合，从而在慢性EAE中产生显着的治疗效果和神经保护作用。 感兴趣的是，RTL1000和DRα1-MOG-35-55更有效地治疗雄性小鼠的慢性EAE 雌激素受体（ESR1）在女性中的拮抗作用。 〜600中MIF，D-DT和CD74的评估 受试者临床研究（待在PNA中出版）表明，具有高表达基因型的男性受试者 对于MIF（和D-DT）而言，逐渐发展为渐进的MS的风险增加。这种独特的观察使 用RTL1000或DRα1-MOG-35-55对男性的早期治疗可能会阻止转化为 进行性MS和可能有效地治疗患有进行性疾病的MS受试者。 FDA IND 批准DRα1-MOG-35-55临床前研究将允许对所有MS受试者进行治疗 HLA类型由于其非晶状体，普遍的表达而被所有人类耐受性，因此 可以注射没有组织打字的情况。更重要的是，我们已经证明了RTL1000和 DRα1-MOG-35-55构建体还可以治疗实验小鼠模型中的其他CNS条件 实验性中风，血管性痴呆，创伤性脑损伤和甲基苯丙胺诱导的认知 残疾，从而为发展这些毁灭性疾病的退伍军人提供了一种新颖的潜在疗法。