Applications of Genomics Derived Characteristics for Evolutionary and Functional studies and for Development of Novel Diagnostics and Therapeutics

基因组学衍生特征在进化和功能研究以及新型诊断和治疗方法开发中的应用

• 批准号: RGPIN-2019-06397
• 负责人: Gupta, Radhey
• 金额: $ 3.42万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744177
• 关键词: Applications; Genomics; Derived; Characteristics; Evolutionary

Microorganisms play vital roles in all aspects of life including recycling of organic materials, nitrogen fixation, photosynthesis, waste decomposition, bioremediation, production of antibiotics and other important compounds, as well as major determinants of human health and diseases. In view of their central roles in health care, agriculture, mining, fishing and other areas, it is important to develop reliable means for distinguishing different groups of microorganisms. However, most of the bacterial groups are currently distinguished from each other only on the basis of their branching in the 16S rRNA trees. As 16S sequence information does not, in itself, provide prediction of phenotypic trait(s) for most groups, no group-specific molecular or biochemical properties are known. For a reliable and comprehensive understanding of the biological properties of diverse groups of microorganisms, it is critically important to identify evolutionarily conserved traits that are uniquely shared by specific groups of interest and which can distinguish them from all others. Genome sequences provide a unique and definitive resource for discovering novel molecular markers that are specific for each group. Using genome sequences, my group has pioneered the discovery of two types of molecular markers, Conserved Signature Indels (CSIs) and Conserved Signature Proteins (CSPs), which are uniquely found in specific groups of organisms. As the genotype specifies phenotype, these molecular markers will provide important means for discovering novel biochemical/biological properties uniquely shared by each group of organisms and for development of novel diagnostics and therapeutics aimed at these organisms. During the next 5 years, our work in this area will use genome sequences to comprehensively investigate three important groups of bacteria viz. Pseudomonadales, Lactobacillales and Bacillales. These groups harbor many "priority human pathogens," several major plant pathogens, as well as other bacteria playing key roles in the dairy and agriculture industries. We will identify multiple reliable characteristics specific for different disease-causing as well as beneficial bacteria that are part of these large groups, thereby providing important means for discovering novel biochemical traits of these bacteria and improving the means for their identification. Additionally, an important objective of this proposal is to test/establish the proof of principle that the CSIs in protein structures can be targeted for development of novel cell-growth inhibitory compounds. The establishment of this concept can provide a vast resource of new classes of drugs/inhibitors targeting the CSI-containing organisms. Overall, the work proposed here should greatly advance our understanding of a number of important groups of microorganisms and the applications of these findings should lead to a significant reduction in the health, agricultural and economic burden caused by these bacteria.

微生物在生活的各个方面都起着至关重要的作用，包括氮，氮固定，光合作用，废物分解，生物修复，抗生素和其他重要化合物的产生以及人类健康和疾病的主要决定因素。鉴于它们在医疗保健，农业，采矿，捕鱼和其他领域中的主要作用，重要的是要开发可靠的方法来区分不同的微生物群体。但是，目前，大多数细菌组仅根据16S rRNA树的分支而彼此区分。由于16S序列信息本身并不能为大多数组提供表型性状的预测，因此，没有群体特异性的分子或生化特性。为了对各种微生物群体的生物学特性有可靠而全面的理解，确定在进化上保守的特征至关重要，这些特征由特定的利益群体独特地共享，并可以将它们与其他所有人区分开来。基因组序列为发现针对每组特定的新分子标记提供了独特而确定的资源。使用基因组序列，我的小组率先发现了两种类型的分子标记物，保守的特征插入（CSIS）和保守的特征蛋白（CSP），这些蛋白（CSP）在特定的生物体中独特地发现。正如基因型指定表型的那样，这些分子标记物将为发现每组生物体独特地共享新型的生化/生物学特性，并开发针对这些生物体的新型诊断和治疗剂的发展。在接下来的5年中，我们在该领域的工作将使用基因组序列来全面研究三个重要的细菌组。假单胞菌，乳杆菌和芽孢杆菌。这些群体具有许多“优先人类病原体”，几种主要的植物病原体以及其他细菌在乳制品和农业行业中起关键作用。我们将确定这些大型群体一部分的多种可靠特征以及有益细菌的特定特征，并为发现这些细菌的新生化特征提供了重要手段，并改善了其鉴定的手段。此外，该提案的一个重要目标是测试/确定原理证明蛋白质结构中的CSIS可以针对新型细胞增长抑制化合物的发展。这个概念的建立可以提供针对含CSI的生物的大量新的药物/抑制剂。总体而言，这里提出的工作应大大提高我们对许多重要的微生物群体的理解，这些发现的应用应导致这些细菌引起的健康，农业和经济负担大大减轻。