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Microphysiological Human Tissue Systems for Monitoring of Genome Editing Outcomes

用于监测基因组编辑结果的微生理人体组织系统

基本信息

批准号：
9810917
负责人：
Nenad Bursac
金额：
$ 66.82万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9810917
关键词：
Address Affect Animal Model Architecture Bacteria Biology CRISPR/Cas technology Cell Line Cell Survival Cells Cellular Immunity Cellular Metabolic Process Clinical Communicable Diseases DNA Sequence Alteration Development Disease Disease model Duchenne muscular dystrophy Ensure Evaluation Genes Genetic Diseases Genome Genome Stability Genome engineering Genomics Goals Human Human Biology Human Engineering Human Genome Humoral Immunities Immune Immune response Immune system Immunity Injury Methods Modification Monitor Mus Muscle Muscle Development Myocardium Natural regeneration Non-Viral Vector Nucleic Acids Outcome Physiological Physiology Pluripotent Stem Cells Prevalence Proteins Research Personnel Role Severities Site Site-Directed Mutagenesis Skeletal Muscle Stem cells System Technology Therapeutic Tissue Engineering Tissues Translating Translations Treatment Efficacy United States National Institutes of Health Viral adaptive immune response adverse outcome design drug discovery experimental study genome analysis genome editing genome integrity genome-wide human disease human tissue insight microphysiology system muscle form new technology novel strategies response somatic cell gene editing therapy outcome tissue regeneration tool vector

项目摘要

Abstract: Genome editing technologies have significant potential to treat a variety of devastating human diseases and disorders. However, there are a number of challenges that genome editing therapies must overcome to reach their full promise. Specifically, there are many possible adverse consequences that are unique to genome editing tools, such as genome integrity, immune responses, and loss of therapeutic efficacy due to cell turnover, for which there are currently are no optimal systems for rigorous assessment. Moreover, these consequences are unique to human physiology, genome sequence, and immune systems, and therefore typical animal models are not completely informative. To address this unmet need, we have assembled a team of collaborative investigators that have developed advanced genome editing strategies and methods for engineering human microphysiological tissue systems that recapitulate human physiology and function, with an emphasis on skeletal and cardiac muscle. We will combine these technologies in this proposal to systemically evaluate tissue physiology, genomic alterations, tissue regeneration, and immune response in response to various genome editing strategies and delivery methods. Specifically, this will include comprehensive and unbiased mapping of unintended modifications to human genome sequences, including at on-target and off-target sites. We will also determine the role of resident tissue stem cells, cell turnover, and tissue injury and regeneration in the stability of genome editing. Finally, we can incorporate immune cells into these microphysiological tissues to understand the consequences of immunity to bacteria-derived genome editing components. Collectively, this proposal will develop a platform to systematically address the most significant challenges to realizing the transformative potential of genome editing therapies in human tissues.

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