Towards a Structural Systems Biology Approach for Anti-Trypanosomal Therapeutics

抗锥虫治疗的结构系统生物学方法

基本信息

批准号：
8122149
负责人：
Rommie E Amaro
金额：
$ 3.3万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2011-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8122149
关键词：
Accounting African African Trypanosomiasis Age-Years Algorithms Area Award Binding Biological Process Biology Blood Circulation Central America Chagas Disease Chemistry Collaborations Complex Computer Assisted Country Development Development Plans Disease Drug Delivery Systems Drug Design Faculty Financial Support Goals Grant Homologous Gene Human Insecta Institution Investigation K22 Award Lead Length Ligands Ligase Medical Medical Research Mentors Messenger RNA Methodology Methods Mitochondrial RNA Multiprotein Complexes Parasites Pathway interactions Pharmaceutical Preparations Physics Play Positioning Attribute Postdoctoral Fellow Process Proteins Protocols documentation RNA RNA Binding RNA Editing RNA-Binding Proteins Research Research Personnel Research Training Resolution Risk Role Scheme Science Secure Shadowing (Histology)South America Structure System Systems Biology Therapeutic Time Translations Tropical Disease Trypanosoma Trypanosoma brucei brucei UDPglucose-Hexose-1-Phosphate Uridylyltransferase United States National Institutes of Health Uracil Nucleotides Validation Vision Work base biological systems career career development computer studies design drug discovery experience flexibility frontier improved inhibitor/antagonist innovation insertion/deletion mutation insight interest member mitochondrial messenger RNA molecular dynamics molecular recognition next generation novel strategies premature professor protein function receptor simulation therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The trypanosomes are a group of parasites that cause several devastating tropical diseases, including African sleeping sickness in African and Chagas' disease in Central and South America. Each year, millions of people in the poorest countries are at risk for and suffer from these diseases. Yet, effective drugs to treat these diseases are greatly lacking. The trypanosome parasites possess a unique biological process wherein their mitochondrial RNAs are extensively edited before translation can occur. This process takes places in a large supramolecular complex known as the editosome. As humans do not undergo the same extensive editing of their mitochondrial RNAs, they do not possess this editing complex, thus, it is an ideal drug target. The overall goals of my work are to develop anti-trypanosomal therapeutics that target various parts of the editosome machinery. Physics- and chemistry-based computer-aided drug design methodologies can assist us in our efforts to design more effective drugs that will thwart the parasites' efforts to survive. My main career goals are to become a tenured, endowed professor at a R1 research institution and to have a vibrant, productive, and diverse research group. As a faculty member, my vision is to drive computer-aided drug design towards a systems biology approach, where multiple proteins, and the RNAs they bind, are targeted - thus challenging the "one-target, one-disease, one-drug" paradigm. The new approaches I envision will integrate multiple time and length scales and take explicit advantage of the new structural information these algorithms yield, in order to create new and improved drugs to treat a variety of diseases. These investigations will push important frontiers in our understanding of biology, ultimately opening new pathways to more effective therapeutics. In this application, I outline a training, research, and career development plan that I believe will transform the field of computer-aided drug design and play an essential role in my development as an independent investigator. Importantly, the K22 award will allow me to focus more of my energy on achieving these innovative scientific goals in the initial faculty years, which will in turn greatly improve my chances of securing an NIH R01 grant and becoming a tenured professor. The trypanosomes are the causative agents of several devastating tropical diseases. Each year, millions of people are at risk for and suffer from these diseases, yet, effective drugs to treat these diseases are lacking. The goals of my work are to develop new and improved computer-aided drug design methods, enabling the discovery and development of better drugs against these diseases.

描述（由申请人提供）：锥虫是一组寄生虫，可引起多种毁灭性热带疾病，包括非洲的非洲昏睡病和中美洲和南美洲的恰加斯病。每年，最贫穷国家有数百万人面临这些疾病的风险并遭受其痛苦。然而，治疗这些疾病的有效药物却非常缺乏。锥虫寄生虫具有独特的生物过程，其中它们的线粒体 RNA 在翻译发生之前被广泛编辑。这个过程发生在一个称为编辑体的大型超分子复合物中。由于人类不会对线粒体 RNA 进行同样广泛的编辑，因此他们不具有这种编辑复合物，因此，它是理想的药物靶点。我工作的总体目标是开发针对编辑体机制各个部分的抗锥虫疗法。基于物理和化学的计算机辅助药物设计方法可以帮助我们设计更有效的药物来阻止寄生虫的生存。我的主要职业目标是成为 R1 研究机构的终身教授，并拥有一个充满活力、富有成效和多元化的研究团队。作为一名教员，我的愿景是推动计算机辅助药物设计走向系统生物学方法，其中多种蛋白质及其结合的 RNA 是有针对性的 - 从而挑战“单一目标、一种疾病、一种药物”范例。我设想的新方法将整合多个时间和长度尺度，并明确利用这些算法产生的新结构信息，以创造新的和改进的药物来治疗各种疾病。这些研究将推动我们对生物学理解的重要前沿，最终为更有效的治疗开辟新途径。在这份申请中，我概述了一项培训、研究和职业发展计划，我相信该计划将改变计算机辅助药物设计领域，并在我作为独立研究者的发展中发挥重要作用。重要的是，K22 奖项将使我能够在最初的教职生涯中将更多的精力集中在实现这些创新的科学目标上，这反过来又会大大提高我获得 NIH R01 资助并成为终身教授的机会。锥虫是几种毁灭性热带疾病的病原体。每年，数百万人面临这些疾病的风险并遭受其痛苦，然而，缺乏治疗这些疾病的有效药物。我的工作目标是开发新的和改进的计算机辅助药物设计方法，从而能够发现和开发更好的药物来对抗这些疾病。