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.

芥子气和与芥子气有关的化合物是烷基化剂，可引起严重的上皮和深层组织损伤