Combination ribonucleic acid nanotechnologies to simultaneously study the multitude of mechanistic pathways found in complex diseases

慢性病是一种复杂而难以研究的疾病。一个单一的生物学异常可以级联成其他问题，使细胞和组织容易受到更多的伤害。目前，当试图研究慢性疾病的原因时，研究人员利用小分子来阻止或激活我们认为导致疾病的细胞内的某些机械过程。一些流程包含多个步骤，其中一些步骤与其他流程共享，这就形成了一个广泛的网络。这种重叠使得很难专门针对一个进程而不意外地激活另一个进程。此外，鉴于慢性疾病中功能障碍过程的多样性令人难以置信，许多感兴趣的目标缺乏可以提供控制的相应小分子。由于缺乏有针对性的控制，我们对哪些功能失调的细胞过程导致慢性疾病的理解存在知识缺口。为了弥合这一差距并揭示隐藏的疾病机制，迫切需要能够控制难以捉摸的过程的新工程工具。此外，许多疾病是由于多个过程的失败而引起的。因此，这些工具还必须能够同时控制许多过程，以进行有意义的研究。我们的长期愿景是发现功能失调过程的组合导致慢性疾病。我们将利用我们在多伦多大学医学机器学习中心、生物医学工程研究所和免疫学系的跨学科地位来实现这一愿景。为了开始这些研究，我们需要新的工程工具，使我们能够精确地操纵细胞内的任何过程，以模拟疾病的进展。因此，作为我们的出发点，这个发现补助金计划将创造一种新的纳米技术，当管理到细胞，可以调整任何过程的研究目的。然后，我们观察这些变化的结果，以了解这些过程如何影响疾病的发生和进展。这种纳米技术是以小颗粒的形式进入细胞并传递核酸。核酸是细胞可以读取和遵循的指令集。在纳米技术递送核酸后，细胞将遵循指令，指令告诉它们如何改变其内部过程以模仿疾病。我们将筛选许多不同的核酸，以发现哪种指令导致疾病。通过这种方式，我们将逐步推导出导致不同疾病的序列。这项研究将推进我们对疾病发生原因和进展方式的基本理解。就加拿大人的利益而言，该方案培养了具有化学（纳米技术的有机合成）、细胞生物学（大规模筛选）、分析方法（细胞观察和数据收集）和机器学习（先进疾病建模）技能的高素质人才。

Chronic diseases are complex and difficult to study. A single biological aberration can cascade into additional problems, leaving cells and tissues vulnerable to more damage. Currently, when trying to study the cause of chronic diseases, researchers make use of small molecules that can block or activate certain mechanistic processes inside cells that we believe cause disease. Some processes contain multiple steps, and some of these steps are shared with other processes, which creates an extensive network. This overlap makes it difficult to exclusively target one process without accidentally activating another one. Moreover, given the incredible diversity of malfunctioning processes in chronic diseases, many targets of interest lack a corresponding small molecule that can provide control. Because of this lack of targeted control, there is a knowledge gap in our understanding of which malfunctioning cellular processes contribute to chronic disease. To bridge this gap and reveal hidden insights into the mechanics of diseases, new engineering tools capable of controlling elusive processes are desperately needed. Furthermore, many diseases arise from the failure of multiple processes. Thus, these tools must also have the ability to control many processes at once to perform meaningful studies. Our long-term vision is to discover what combination of malfunctioning processes lead to chronic diseases. We will leverage our interdisciplinary position in the University of Toronto's Centre for Machine Learning in Medicine, Institute of Biomedical Engineering and Department of Immunology to achieve this vision. To begin these studies, we require new engineering tools that allow us to precisely manipulate any process inside a cell to mimic the progression of disease. Thus, as our starting point, this Discovery Grant program will create a new nanotechnology that, when administered to cells, can adjust any process for research purposes. We then observe the outcome of these changes to understand how these processes influence the initiation and progression of disease. This nanotechnology is in the form of small particles that enter cells and deliver nucleic acids. Nucleic acids are instruction sets that cells can read and follow. After the nanotechnology delivers the nucleic acids, the cells will follow the instructions, which tell them how to change their internal processes to mimic a disease. We will screen many different nucleic acids to discover which instruction lead to disease. In this way, we will deduce the step-by-step sequences that lead to different diseases. This research will advance our fundamental understanding of why diseases occur and how they progress. In terms of benefits to Canadians, this program creates highly qualified personnel with skills in chemistry (organic synthesis of nanotechnology), cell biology (large-scale screens), analytical methods (cell observation and data collection), and machine learning (advanced disease modelling).