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.

项目摘要/摘要进化是人类发展以及对人类健康的最大挑战的基础。在整个生命之树，癌症和传染性病毒，原核生物和真核生物中都存在于复合物中可以促进或抑制疾病进展和治疗性抗性的竞争景观。异源细胞种群的惊人多样性提出了有关如何对抗药物的现有问题抗性演变。解决这个问题的协同方法是试图反向工程师不断发展生物系统。即，在选择后，我们分离了耐药细胞，试图确定什么引起耐药性并治疗抗性状态。这种策略导致“阻力跑步机” 发生抗性进化，新药对抗耐药性，然后再出现抗药性 - 一个过程直到我们用完有效的代理。我们相信，我们不应该打击进化，而是应该利用它。我们建议采用一种“前进工程”方法，试图创建新的范式控制和理解进化。通过创建双开关基因驱动器，我们可以使用工程建立人群的设计可以通过模型驱动治疗干预措施来指导其进化。在本质，我们将使异源细胞群体的进化发展到可根除的结果。这会在诊所中转移范式，但是，通过建立这些细胞系统，用化学和生物学和定量建模他们的动态，我们也可以在我们采用时“构建”进化巨型迈向控制它。