Developing an integrative bioinformatic approach for the selection of therapeutic targets

与人类生物学相关的基因组和结构数据的爆炸式增长，以及用于查询这些数据的计算工具的不断发展，为研究人类生物学提供了新的机会。这个研究项目的目标是将这个范例应用到目标发现过程中。我们将开发新的方法来鉴定蛋白质靶点，既与疾病有明确的遗传联系，又在结构上可药物。我们的长期目标是扩展方法和经验教训，在原子和遗传水平上进一步整合生物过程基础的分子电路。拥抱开放科学的概念将促进我们的发现在我们现有的合作者网络之间和之外的传播，并最大限度地发挥我们的影响。******目标蛋白的选择是大多数药物发现项目的第一步，它决定了该项目将成功还是失败地为患者提供新药。如果目标的三维结构在化学上不容易处理，这个程序在开始之前就注定要失败。同样重要的是，有必要确定目标蛋白在疾病途径中的致病和基本作用。为了提高药物发现的成功率，需要更好地了解靶标选择过程。******大数据开始涌入生物医学界，是一种变革性的信息来源。我的研究项目的全球目标是整合结构和基因组学数据来研究人类生物学，重点是健康和疾病中的转录调节。在本提案中，我们将关注基因表达的调控，这是一个对多种疾病途径至关重要的生物学领域，但却抵制了大多数药物发现的努力，我们将把来自癌症患者的染色体畸变和合成致命性筛选（基因A的缺失导致对基因B的依赖）的大型数据库结合起来，以确定肿瘤特异性遗传脆弱性，并揭示药物应该靶向的蛋白质。我们还将分析数千种人类蛋白质高分辨率结构表面的结合袋的可药物性和结构多样性，以确定物理上可以被药物靶向的靶标。我们将在蛋白质网络和信号通路的背景下，绘制出能够、应该和被药物靶向的蛋白质，并确定迄今为止被忽视的新的高优先级靶标。参与本项目的学生将获得结构生物信息学和计算基因组学方面的专业知识，并将受益于由结构生物学家、生物化学家、细胞生物学家组成的跨学科、开放的环境。他们还将能够与多伦多市中心充满活力的当地生物信息学社区分享和学习。

The exploding volume of genomic and structural data related to human biology, and the continuous development of computational tools to interrogate this data generate novel opportunities to investigate human biology. The goal of this research program is to apply this paradigm to the target discovery process. We will develop novel methodologies to identify protein targets that both have clear genetic linkage to disease, and are structurally druggable. Our long-term goal is to expand methodologies and lessons learnt from this exercise to further integrate at the atomic and genetic level the molecular circuitry that underlies biological processes. Embracing an open science concept will facilitate the dissemination of our findings across and beyond our existing network of collaborators, and maximize our impact.******Selection of a target protein is the first step in most drug discovery programs, and determines whether the program will succeed or fail to deliver a new drug to patients. If the three-dimensional structure of the target is not chemically tractable, the program is doomed before it started. Equally important is the necessity to establish a causative and essential role of the targeted protein in the disease pathway. To increase the success rate in drug discovery, the target selection process needs to be better informed.******Big Data that started flooding the biomedical community is a transformative source of information. The global goal of my research program is to integrate structural and genomics data to investigate human biology, with a focus on the regulation of transcription in health and disease. In this proposal, while focusing on the regulation of gene expression, an area of biology that is central to multiple disease pathways but has resisted most drug discovery efforts, we will interface large databases of chromosomal aberrations from cancer patients and synthetic lethality screens (where deletion of Gene A causes dependency on Gene B for survival) to identify tumor-specific genetic vulnerabilities, and reveal proteins that should be targeted by drugs. We will also analyze the druggability and structural diversity of binding pockets at the surface of thousands of high-resolution structures of human proteins to identify targets that physically can be targeted by drugs. We will map proteins that can, that should, and that are targeted by drugs in the context of protein networks and signalling pathways, and identify novel high-priority targets that so far have been neglected. Students working on this project will acquire a rarely combined set of expertise in structural bioinformatics and computational genomics, and will benefit from a cross-disciplinary, open space environment composed of structural biologists, biochemists, cell biologists. They will also be able to share with and learn from the vibrant local bioinformatics community of downtown Toronto.