"Clinical Trials" on a Premature Vascular Aging-on-a-Chip Model

血管过早老化芯片模型的“临床试验”

• 批准号: 10691727
• 负责人: Yu Shrike Zhang
• 金额: $ 13.53万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10691727
• 关键词: Adult; Affect; Aging; Astronauts; Biological; Biomimetics; Bioreactors; Blood Vessels; Cell Density; Cells; Child; Clinical Trials; Clinical Trials Design; Developmental Biology; Endothelial Cells; Environment; Fibroblasts; Formulation; Future; Genetic Diseases; International; Knowledge; Laboratory Study; Life; Medical; Methodology; Microgravity; Mission; Modeling; Modification; Pathologic; Patients; Periodicity; Persons; Phenotype; Physiological; Planet Earth; Premature aging syndrome; Progeria; Smooth Muscle Myocytes; Stretching; Syndrome; System; Technology; Therapeutic Intervention; Tissues; biofabrication; bioink; bioprinting; grasp; premature; preventive intervention; space station

Abstract Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder that results in premature and accelerated aging, while accumulation of progerin also occurs during physiological aging. Our paratal project seeks to optimize a biomimetic HGPS-on-a-chip system generated with patient-derived fibroblasts (FBs), smooth muscle cells (SMCs), and endothelial cells (ECs) that allow application of relevant cyclic stretch for performing ‘clinical trials’ or informing clinical trial designs for HGPS patients. Given the unique microgravity environment of the International Space Station-National Lab (ISS-NL), which has been shown before to pose various negative effects on vascular cell phenotypes, this supplement further aims at developing a methodology to enable in-space bioprinting of multi-layered, high-cell-density, bioreactor-integrated vascular conduits through Techshot’s BioFabrication Faclity (BFF) at the International Space Station-National Laboratory (ISS-NL), and studying premature vascular aging under microgravity. Successful completion of the proposed supplement project will be transformative in multiple aspects. First, it will demonstrate a unique in-space BFF utility through the use of new bioink formulations for the bioprinting of a new tissue type not previously done. Yet, while we target vascular bioprinting, we anticipate that the technology is applicable to many other tissue types with necessary modifications. Second, the biological study will benefit life both in space and on Earth. Vascular aging is a pressing medical problem that affects millions of people, and is potentially also a major pathological manifestation for astronauts especially for future deep-space missions. Under our hypothesis that vascular conduits bioprinted with HGPS cells will manifest a pathologically relevant premature aging phenotype that is more severely affected by the space microgravity environment than those with healthy cells and those on Earth, we anticipate grasping additional fundamental knowledge regarding the underlying mechanisms of vascular aging in both children and adults in association with developmental biology, which will further instruct prevention and therapeutic interventions in the future in HGPS and beyond.

摘要 Hutchinson-Gilford早衰综合征（HGPS）是一种遗传性疾病， 老化，而早老蛋白的积累也发生在生理老化过程中。我们的paratal项目旨在 优化用患者来源的成纤维细胞（FB）生成的仿生HGPS-on-a-chip系统，平滑 肌肉细胞（SMC）和内皮细胞（EC），其允许应用相关的周期性拉伸以执行 “临床试验”或告知HGPS患者的临床试验设计。鉴于独特的微重力环境 国际空间站-国家实验室（ISS-NL），以前曾被证明可以构成各种 对血管细胞表型的负面影响，该补充进一步旨在开发一种方法， 使多层、高细胞密度、生物反应器集成的血管导管的空间生物打印成为可能， Techshot在国际空间站国家实验室（ISS-NL）的生物制造设施（BFF），以及 研究微重力下的血管过早老化圆满完成拟议补编 该项目将在多个方面进行变革。首先，它将展示一个独特的空间BFF实用程序， 使用新的生物墨水制剂来生物打印以前没有做过的新组织类型。然而，当我们 靶向血管生物打印，我们预计该技术适用于许多其他组织类型， 必要的修改。第二，生物学研究将有益于空间和地球上的生命。血管 衰老是一个影响数百万人的紧迫医学问题，也是一个潜在的主要病理学问题。 特别是对于未来的深空任务。根据我们的假设， 用HGPS细胞生物打印的导管将表现出病理学相关的早衰表型， 受太空微重力环境的影响比那些健康细胞和那些 地球，我们期望掌握更多的基本知识，关于潜在的机制， 儿童和成人血管老化与发育生物学的关系，这将进一步指导 预防和治疗干预在未来的HGPS和超越。