Rational design of DNA Nanostructures for disease diagnostics and prognostics

正如“组学”革命充分表明的那样，疾病通过无数微妙的行为变化在细胞水平上表现出来。例如，免疫细胞在遇到病原体后改变转录模式，癌细胞对化疗的反应也是如此。这些模式使得能够识别一组广泛的表达特征，这些特征具有诊断从传染病和糖尿病到癌症和耐药性等各种疾病的潜力。然而，快速准确地识别这些特征签名的技术尚未取得成果。基于杂交的技术在并行识别大量RNA序列方面表现出色，但灵敏度较低；相反，酶反应实现了对痕量靶标浓度的快速检测，但缺乏分辨这些表达特征中明显的细微变化的分辨率。这个项目的目标是将这两种方法结合起来，利用合理设计的杂交系统的特异性和酶系统的敏感性。学生将熟练掌握DNA纳米结构的模拟指导设计，在分层尺度上对DNA相互作用进行建模，以设计所需的序列、结构域和整个反应动力学。学生将把这些生物设计原理应用于疾病的诊断和预后。

As the "omics" revolution has made abundantly clear, diseases manifest at the cellular level through myriad subtle changes in behaviour. For example, immune cells alter transcription patterns after encountering pathogens, as do cancerous cells in response to chemotherapeutics. These patterns have allowed the identification of a broad set of expression signatures with diagnostic potential for conditions ranging from infectious disease and diabetes to cancer and drug resistance. However, the technology to quickly and accurately recognize these characteristic signatures has yet to reach fruition. Hybridization-based technologies have excelled at ultraspecific recognition of numerous RNA sequences in parallel yet exhibit poor sensitivity; conversely, enzymatic reactions have achieved rapid detection of trace target concentrations yet lack the resolution to discern the subtle changes in evident in these expression signatures. The goal of this project will be to combine these two approaches, leveraging the specificity of rationally-designed hybridization systems with the sensitivity of enzymatic systems. The student will become skilled in the simulation-guided design of DNA nanostructures, modelling DNA interactions at hierarchical scales to engineer the desired sequence, domain, and whole-reaction dynamics. The student will apply these BioDesign principles to the diagnosis and prognosis of disease.