Translation & trials: advancing medical countermeasure development

翻译

• 批准号: 10682633
• 负责人: Kurt Lu
• 金额: $ 63.44万
• 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/10682633
• 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; Epithelium; Erythema; Exposure to; Foundations; Goals; Harvest; Human; Human Subject Research; Immune; Immune mediated destruction; Immune system; Immunophenotyping; Induration; Inflammation; Inflammatory; Injury; MMP9 gene; Macrophage; Mechlorethamine; Mediating; Medicine; 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; Universities; Vesicants; Vitamin D; absorption; biomarker signature; cytokine; efficacy evaluation; efficacy testing; experience; exposed human population; human tissue; immune activation; immune cell infiltrate; in vivo; information gathering; injured; innovation; insight; medical countermeasure; molecular marker; monocyte; nonhuman primate; novel; particle; 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.

芥子气和芥子气相关化合物是烷化剂，可导致严重的上皮和深层组织 以急性炎症、硬结、水肿和接触后起泡为特征的损伤。底层 氮芥（NM）和硫芥（SM）暴露后的组织损伤机制是复杂的。 在最初的皮肤直接损伤后，免疫细胞的涌入为突破提供了防御。 但会产生不利的炎症，最终导致免疫风暴， 组织损伤SM的历史使用表明，其后果超出了皮肤表面。我们 一组研究表明，通过用高剂量维生素D全身抑制活化的巨噬细胞， 局部皮肤和更深的组织损伤。鉴于芥子气暴露造成的全部伤害可归因于 有毒物质和免疫系统的活动，它可能是天真的认为，一个单一的对策 能够充分全面地缓解芥末的影响。我们将利用我们在NM方面的经验 和SM，以及从人体内NM暴露和大型动物中SM暴露中获取库存组织，以作为 基础来解开皮肤隔室与免疫隔室中的信号。芥末暴露皮肤 将外植体进行免疫表型分析，并将收获的培养物上清液用于刺激 幼稚外周血免疫细胞。我们的人类芥末皮肤外植体和上清液（MuSES）实验 设置近似人体皮肤在体内的特征，暴露于SM，并将使研究， 皮肤和免疫区室产生炎症因子。来自MuSES的炎症特征将被 使用来自我们在经历癌前病变的现场治疗的患者中的体内人类临床试验的组织进行验证。 皮肤护理鉴于皮肤表型反应的显著相似性，我们可以收集信息 来测试我们的两种对策。临床结局加上新的 标志性分子靶点将促进5-FU患者的概念验证（POC）临床试验（延迟开始， 3-5年）。我们的对策策略是用维生素C阻断皮肤浸润免疫细胞的激活， D3或用PLGA-免疫修饰微粒阻断它们进入皮肤。这种综合方法旨在 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。的目标 该项目的目的是更好地了解皮肤和免疫系统的反应， 组织和试验来发展医学对策