Translation & trials: advancing medical countermeasure development

翻译

• 批准号: 10490423
• 负责人: Kurt Lu
• 金额: $ 65.84万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490423
• 关键词: Acute; Address; Alkylating Agents; Animal Model; Animals; Antimetabolites; Apoptosis; Area; Binding; Biological Markers; Biology; Biopsy; Blood; Body Surface Area; Bone Marrow Suppression; Bulla; Caring; Cell Death; Cells; Cessation of life; Cholecalciferol; Clinical; Clinical Medicine; Clinical Trials; Complex; Coupled; DNA Damage; DNA biosynthesis; Dermatologic; Development; Disease; Dose; Edema; Epithelial; Erythema; Exposure to; Fluorouracil; Foundations; Goals; Harvest; Human; Human Subject Research; Immune; Immune mediated destruction; Immune system; Immunophenotyping; Induration; Inflammation; Inflammatory; Injury; Institutes; Lead; MMP9 gene; Mechlorethamine; Mediating; Methods; Modeling; Molecular Profiling; Molecular Target; Mustard; Mustard Gas; Outcome; Outcome Measure; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Production; Reaction; Redness; Resources; Role; Signal Transduction; Skin; Skin Manifestations; Source; Surface; Swelling; TNF gene; Technology; Testing; Time; Tissue Banks; Tissues; Transforming Growth Factor beta; Translations; Treatment Protocols; Tumor-infiltrating immune cells; Universities; Ursidae Family; Vesicants; Vitamin D; absorption; base; biomarker signature; cytokine; efficacy testing; experience; exposed human population; human tissue; immune activation; in vivo; injured; innovation; insight; macrophage; medical countermeasure; molecular marker; monocyte; nonhuman primate; novel; peripheral blood; premalignant; prevent; receptor; release factor; response; skin barrier; skin cancer prevention; standard of care; tissue injury; transcriptome sequencing

Mustard gas and mustard-related compounds are alkylating agents that cause severe epithelial and deep tissue injury characterized by acute inflammation, induration, edema, and blistering upon contact. The underlying mechanism of tissue damage following exposure to nitrogen mustard (NM) and sulfur mustard (SM) is complex. After the initial direct injury to the skin there is an influx of immune cells that provide a defense to a breached epithelium but can produce unfavorable inflammation culminating in an immune storm that sets off a cascade of tissue injury. Historic use of SM demonstrates that the consequences extend beyond surfaces of the skin. Our group has shown by suppressing activated macrophages systemically with high dose vitamin D can ameliorate both local skin and deeper tissue injury. Given that the totality of injury from mustard exposure is attributable to the toxic agent and the activities of the immune system, it may be naive to consider that a single countermeasure can adequately and comprehensively mitigate the effects of mustard. We will leverage our experience with NM and SM, and access to banked tissue from in vivo NM exposure in humans and SM in large animals, to serve as a foundation to unravel the signals in the skin compartment vs. the immune compartment. Mustard exposed skin explants will be immunophenotyped and the harvested culture supernatants will be used to stimulate activation of naïve peripheral blood immune cells. Our human Mustard Skin Explant and Supernatant (MuSES) experimental setup approximates features of human skin in vivo, exposed to SM and will enable studies that delineate inflammatory factor production by the skin and immune compartments. Inflammation profiles from MuSES will be validated using tissue from our in vivo human clinical trials in patients undergoing field treatment for precancerous skin treatments. Given the remarkable resemblance of the skin phenotype reaction, we can gather information from in vivo human exposure models to test our two countermeasures . Clinical outcomes coupled with novel signature molecular targets will facilitate proof-of-concept (POC) clinical trials in 5-FU patients (delayed start to years 3-5). Our countermeasure strategies are to block the activation of skin infiltrating immune cells with vitamin D3 or block their entry into the skin with PLGA-immune modifying microparticles. This combined approach is aimed at limiting the surge of cytokines and inhibiting downstream tissue matrix factors released in the skin. The goals of this project are to better understand reactions of the skin and immune system using a combination of human tissue and trials to develop medical countermeasures.

芥末气和与芥末相关的化合物是引起严重上皮和深组织的烷基化剂 接触时以急性炎症，诱导，水肿和起泡为特征的伤害。基础 暴露于氮芥末（NM）和硫芥末（SM）后组织损伤的机制很复杂。 最初直接受伤的皮肤受伤后，免疫球会影响违反的防御 上皮，但可能会导致不利的炎症，最终在免疫风暴中导致级联 组织损伤。 SM的历史用途表明，后果范围超出了皮肤的表面。我们的 通过高剂量维生素D系统地抑制激活的巨噬细胞可以改善 局部皮肤和更深的组织损伤。鉴于芥末暴露的全部受伤归因于 有毒药物和免疫系统的活动，认为单一的对策可能是天真的 可以充分，全面地减轻芥末的影响。我们将利用NM的经验 和SM，并从人类的体内接触到大型动物中的体内接触库的组织，以充当 基础是揭开皮肤室中的信号与免疫室的基础。芥末露的皮肤 外植体将进行免疫表型，并将收获的培养上清液用于刺激激活 幼稚的外周血免疫细胞。我们的人类芥末皮外植体和上清液（缪斯）实验 设置近似于人体皮肤的特征，暴露于SM，并将启用描述的研究 皮肤和免疫室的炎症因子产生。来自缪斯女神的炎症特征将是 在接受现场治疗的患者中使用我们体内人类临床试验的组织进行了验证 皮肤治疗。考虑到皮肤表型反应的显着相似之处，我们可以收集信息 从体内人类暴露模型来测试我们的两个对策。临床结果加上新颖 签名分子靶标将促进5-FU患者的概念验证（POC）临床试验（延迟开始为 3-5年）。我们的对策策略是通过维生素阻止皮肤浸润的免疫细胞的激活 D3或用PLGA-rimmune修饰微粒进入皮肤进入皮肤。这种组合方法针对 在限制细胞因子的激增并抑制皮肤中释放的下游组织基质因子。目标 该项目的结合是更好地了解皮肤和免疫系统的反应 组织和试验以发展医学对策。