权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Collaborative Research: GOALI: High-Impact Multiscale Physicochemical Advancements for the Prediction of Transient Dermal Absorption

合作研究：GOALI：预测瞬时真皮吸收的高影响力多尺度物理化学进展

基本信息

批准号：
2124495
负责人：
Gerald Kasting
金额：
$ 29.47万
依托单位：
University of Cincinnati Main Campus
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2124495&HistoricalAwards=false
关键词：
Collaborative Research GOALI Impact Multiscale

项目摘要

This GOALI project will advance the science of skin penetration and, in particular, the prediction of transient dermal absorption for human exposure to chemical agents, whether they are beneficial or hazardous. The former case includes topical drugs and cosmetic benefit agents; the latter includes aerosolized pesticides encountered by farm workers, airborne pollutants encountered by residents in city environments, and trace chemicals encountered by workers in settings such as concrete and metal working. Modeling and simulation has recently become a component of the US FDA’s approval process for generic drug products, which reduces cost and accelerates approval of these products. Global regulatory agencies including US NIOSH have increasingly included modeling as part of their dermal risk assessment process. This project will address two vexing issues plaguing predictions of transient skin absorption: (1) slowly reversible binding of chemicals to skin proteins (especially keratin) complicates the uptake and release profiles of many commonly-encountered chemicals including topical steroids; and (2) gradual dissolution of solid particles deposited on the skin surface or within hair follicles affects absorption of drugs from gels and ointments and dermal absorption of heavy metals leached from airborne pollutants. Results from the project will be incorporated into a publicly available, spreadsheet-based skin penetration program and also a state-of-the-art simulation code for dermal absorption maintained by the GOALI industrial partner, Procter & Gamble. Parts of the research will be incorporated into undergraduate and graduate training in the cosmetic science area at the University of Cincinnati. The educational plan also specifically targets undergraduate research experiences for undergraduate women and underrepresented minority students.This project entails: (1) experimental measurement and broad parameterization of rate constants for keratin binding in the outer skin barrier cells (corneocytes) supported by a rigorous theoretical framework; and (2) development and implementation of interfacial mass transport relationships capable of representing absorption of precipitated solids on the skin. Intellectual merit lies in the identification and resolution of important strategic gaps in the current understanding of dermal absorption, which block progress in these two areas involving multiphase and multiscale transport. A central element of the project is multiscale modeling based on two stages of rigorous coarse graining - from ultrastructural (intracellular) to microscopic (intercellular) to macroscopic (tissue) scales - in resolving slow reversible binding of permeating molecules to stratum corneum keratin, which dramatically affects transport rates. The project will define the reservoir capacity of the skin barrier in theoretically rigorous and pragmatically useful terms, which will open the way to a broad-spectrum ability to accurately predict transient dermal absorption outcomes. The detailed treatment of dissolution-limited absorption will finally resolve dramatically different absorption rates observed for ostensibly similar molecules that have long baffled pharmaceutical and consumer product development efforts and risk assessments related to chemical exposures.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该GOALI项目将推进皮肤渗透科学，特别是预测人类接触化学制剂的瞬时皮肤吸收，无论它们是有益的还是有害的。前一种情况包括局部药物和化妆品有益剂;后一种情况包括农场工人遇到的喷雾杀虫剂，城市环境中居民遇到的空气传播污染物，以及工人在混凝土和金属加工等环境中遇到的微量化学品。建模和仿真最近已成为美国FDA批准仿制药产品过程的一个组成部分，这降低了成本并加快了这些产品的批准。包括US NIOSH在内的全球监管机构越来越多地将建模作为其皮肤风险评估过程的一部分。本计画将探讨两个困扰皮肤短暂吸收预测的问题：（1）化学物质与皮肤蛋白质的缓慢可逆结合（尤其是角蛋白）使许多常见化学物质（包括局部类固醇）的吸收和释放曲线复杂化;以及（2）沉积在皮肤表面上或毛囊内的固体颗粒的逐渐溶解影响药物从凝胶和软膏以及真皮中的吸收吸收从空气污染物中浸出的重金属。该项目的结果将被纳入一个公开的、基于电子表格的皮肤渗透程序，以及由GOALI工业合作伙伴Procter Gamble维护的最先进的皮肤吸收模拟代码。部分研究将纳入辛辛那提大学化妆品科学领域的本科生和研究生培训。该教育计划还特别针对本科女生和代表性不足的少数民族学生的本科研究经验。该项目包括：（1）实验测量和广泛的参数化外层皮肤屏障细胞中角蛋白结合的速率常数（角质细胞）由严格的理论框架支持;以及（2）能够表示沉淀固体在皮肤上的吸收的界面质量传输关系的开发和实施。知识价值在于确定和解决目前对皮肤吸收的理解中的重要战略差距，这些差距阻碍了这两个涉及多阶段和多尺度运输的领域的进展。该项目的一个核心要素是基于两个阶段的严格粗粒化的多尺度建模-从超微结构（细胞内）到微观（细胞间）到宏观（组织）尺度-解决渗透分子与角质层角蛋白的缓慢可逆结合，这极大地影响了运输速率。该项目将以理论上严格和实用的术语定义皮肤屏障的储库容量，这将为准确预测瞬时皮肤吸收结果的广谱能力开辟道路。溶解限制吸收的详细处理将最终解决观察到的表面相似分子的显著不同的吸收率，这些分子长期以来一直困扰着制药和消费品开发工作以及与化学品暴露相关的风险评估。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。