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

• 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
• 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

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.

项目总结/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的基础。 在整个生命之树中，癌症和传染性病毒，原核生物和真核生物都存在于复杂的环境中。 竞争格局，可以促进或抑制疾病进展和治疗耐药性。的 异源细胞群体的惊人多样性提出了关于如何对抗药物的存在问题。 抗性进化解决这个问题的传统方法是试图逆向工程进化 生物系统。即，在选择发生后，我们分离抗性细胞，试图确定 引起耐药性并治疗耐药状态。这种策略导致了一种“阻力跑步机”， 耐药性进化发生，新药对抗耐药性，然后耐药性重新出现--这是一个过程， 直到我们耗尽有效的代理人。我们认为，与其对抗进化论， 利用它。我们建议采用一种"前瞻性工程"的方法，寻求创造新的范例， 控制和理解进化。通过创建一个双开关基因驱动器，我们证明我们可以使用工程 设计以构建其进化可以由模型驱动的治疗干预引导的群体。在 本质上，我们将推动异质细胞群体的进化，走向可根除的结果。这将 但是，通过构建这些细胞系统，用化学方法操纵它们， 生物学，并定量建模其动态，我们也可以"建立理解"进化，因为我们采取 朝着控制它迈出了巨大的步伐。