Model Driven Construction of Dual-switch Selection Gene Drives to Combat Drug Resistance

对抗耐药性的双开关选择基因驱动的模型驱动构建

基本信息

批准号：
9973217
负责人：
Justin Pritchard
金额：
$ 27.43万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
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：
2019-08-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9973217
关键词：
Address Amaze Antibiotics Antiviral Agents Bacteria Biological Biology Bioreactors Bystander Effect CRISPR/Cas technology Cell Therapy Cells Chemicals Chemistry Clinic Clinical Complex Computer Models Development Diffuse Dimerization Disease Progression Drug Delivery Systems Drug resistance Engineering Epidermal Growth Factor Receptor Eukaryota Evolution Failure Genes Goals Health Heterogeneity Human In Vitro Industrialization Industry Joints Lead Left Lentivirus Vector Letters Life Malignant Neoplasms Malignant neoplasm of lung Measurement Measures Modeling Modernization Mutation Natural Selections Nitroreductases Oncogenes Outcome Pharmaceutical Preparations Phosphotransferases Population Population Sizes Process Prodrugs Prokaryotic Cells Public Health Race Resistance Resolution Risk Risk Estimate Running SWI1 Societies Switch Genes System Tacrolimus Binding Protein 1A Techniques Technology Testing Therapeutic Intervention Toxin Trees Virus anti-cancer arm asexual biological systems cell killing cellular engineering combat design dimer drug development drug discovery dual switch selection gene drive engineering design experience fighting novel novel therapeutics prototype simulation suicide gene targeted cancer therapy targeted treatment therapy resistant treadmill

项目摘要

Project Summary/Abstract Evolution underlies both the development of humankind as well as the greatest challenges to human health. Across the tree of life, cancer and infectious viruses, prokaryotes, and eukaryotes exist within complex competitive landscapes that can promote or inhibit disease progression and therapeutic resistance. The amazing diversity of heterogenous cell populations raises existential questions about how to combat drug resistance evolution. The convential approach to this problem is to attempt to reverse engineer evolving biological systems. I.e., after a selection has occurred, we isolate resistant cells, attempt to determine what caused drug resistance and treat the resistant state. This strategy results in a “resistance treadmill” whereby resistance evolution occurs, new drugs combat drug resistance and then resistance re-emerges – a process that occurs until we run out of effective agents. We believe that instead of combatting evolution, we should make use of it. We propose to employ a “forward engineering” approach that seeks to create new paradigms to control and understand evolution. By creating a dual switch gene drive, we posit that we can use engineering design to build populations whose evolution can be guided by model driven therapeutic interventions. In essence, we will drive evolution in heterogenous cell populations towards eradicatable outcomes. This would be paradigm shifting in the clinic, but, by building these cellular systems, manipulating them with chemistry and biology, and quantiatively modeling their dynamics, we can also “build to understand” evolution as we take giant strides towards controlling it.

项目概要/摘要进化既是人类发展的基础，也是人类健康面临的最大挑战。在生命之树上，癌症和传染性病毒、原核生物和真核生物存在于复杂的环境中。可以促进或抑制疾病进展和治疗耐药性的竞争格局。异质细胞群的惊人多样性提出了如何对抗毒品的生存问题解决这个问题的传统方法是尝试对进化进行逆向工程。即，在选择发生后，我们分离出抗性细胞，尝试确定什么。因此，这种策略导致了“耐药跑步机”。耐药性进化发生，新药对抗耐药性，然后耐药性重新出现——一个过程这种情况会一直发生，直到我们用完有效的药物为止。我们认为，我们不应该对抗进化，而应该这样做。我们建议采用“正向工程”方法来创建新的范式。通过创建双开关基因驱动器，我们认为我们可以利用工程学来控制和理解进化。设计建立可以通过模型驱动的治疗干预来指导其进化的群体。本质上，我们将推动异质细胞群的进化，以实现可根除的结果。是临床范式转变，但是，通过构建这些细胞系统，用化学和操作它们生物学，并对其动态进行定量建模，我们还可以“构建理解”进化朝着控制它迈出了巨大的一步。