Integrated in vitro and in silico microphysiological human placental barrier models for reproductive toxicology testing in the pharmaceutical industr

用于制药行业生殖毒理学测试的集成体外和计算机微生理学人胎盘屏障模型

• 批准号: 2776445
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2776445
• 关键词: Integrated; vitro; silico; microphysiological; human

The pharmaceutical industry has a pressing challenge of providing additional advice on the safety of prescription medicines in pregnancy and how ex vivo and in vitro human placental models might be advanced to reproducible human placental test systems (HPTSs), refining a weight of evidence to the guidance given around compound risk assessment during pregnancy [1]. However, all toxicity testing (in vivo, in vitro and in silico) have limitations when extrapolating from animals to the human, or even from cell/tissue to whole organism. Given new ICH S5 revision 3 guidelines on animal use, new in vitro and in silico approaches are needed to improve the evidential value of data alongside other assays; and to build a bigger picture for risk assessment of compounds passing through the testing pipeline in the pharmaceutical industry. Increasing screenability of test compounds within new test systems as well as to demonstrating the robustness of the models is key.This interdisciplinary PhD program addresses a pressing challenge via the development, evaluation and standardisation of a human "placenta on a chip" HPTS, advanced towards a regulated level for use by the pharmaceutical industry to acquire reliable transfer data of test compounds from the maternal to the fetal circulatory systems. The project will appeal to a bioengineering student interested in developing a synthetic human placental barrier and modelling [2] the transmembrane transfer of compounds in an academic and industrial environment. Human primary stem cell trophoblasts [3], forming a true syncytiotrophoblast barrier [4] will be co-cultured with human placental endothelial cells to form a differentiated and polarised placental barrier between opposing maternal and fetal circulatory-phase compartments. Barrier compound clearance studies will be compared to ex vivo data from the human placental dual perfusion model; in vivo animal data; and to known human fetal:maternal plasma ratios for drugs already prescribed in pregnancy. The physical properties of the barrier, including length of diffusional pathway, porosity and fetal-side (acceptor-side) flow will be mathematically modelled for transfer efficacy and tested in the developed barrier system. The candidate will be expected to work flexibly at all locations to develop skills within the Maternal & Fetal Health Research Centre at St Mary's Hospital (supervised by Drs Paul Brownbill and Peter Ruane) and the Department of Mathematics (supervised by Dr Igor Chernyavsky) at the University of Manchester; and the Clinical Pharmacology and Safety Sciences Team at AstraZeneca, Cambridge (supervised by Drs Nicola Powles-Glover and Rhiannon David).

制药行业面临着一个紧迫的挑战，即提供有关妊娠期处方药安全性的额外建议，以及如何将离体和体外人类胎盘模型发展为可重复的人类胎盘试验系统（HPTS），完善妊娠期间化合物风险评估指南的证据权重[1]。然而，所有毒性试验（体内、体外和计算机模拟）在从动物外推至人体，或甚至从细胞/组织外推至整个生物体时均存在局限性。鉴于新的ICH S5修订版3关于动物使用的指导原则，需要新的体外和计算机模拟方法来提高数据的证据价值以及其他检测方法;并为通过制药行业测试管道的化合物的风险评估构建更大的图景。在新的测试系统中增加测试化合物的可筛选性以及证明模型的鲁棒性是关键。这个跨学科的博士课程通过开发，评估和标准化人类“芯片上的胎盘”HPTS来解决紧迫的挑战，制药工业使用的调节水平，以获得测试化合物从母体到胎儿循环的可靠转移数据系统.该项目将吸引生物工程专业的学生，他们有兴趣开发一种合成的人类胎盘屏障，并在学术和工业环境中模拟[2]化合物的跨膜转移。将形成真正合胞体滋养层屏障[4]的人原代干细胞滋养层[3]与人胎盘内皮细胞共培养，以在相对的母体和胎儿循环相区室之间形成分化和极化的胎盘屏障。屏障化合物清除研究将与来自人胎盘双灌注模型的离体数据、体内动物数据以及已知的妊娠期已开处方药物的人胎儿：母体血浆比进行比较。将对屏障的物理性质（包括扩散路径长度、孔隙率和胎儿侧（受体侧）流量）进行数学建模，以确定转运功效，并在开发的屏障系统中进行测试。候选人将在所有地点灵活工作，以发展在圣玛丽医院孕产妇和胎儿健康研究中心的技能（由Paul Brownbill博士和Peter Ruane博士监督）和数学系（由Igor Chernyavsky博士监督）在曼彻斯特大学;和阿斯利康（剑桥）的临床药理学和安全性科学团队（由Nicola Powles-Glover和Rhiannon大卫博士监督）。