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: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=738888
• 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.

微生物在生命的各个方面发挥着至关重要的作用，包括有机材料的回收、固氮、光合作用、废物分解、生物修复、抗生素和其他重要化合物的生产，以及人类健康和疾病的主要决定因素。鉴于微生物在医疗保健、农业、采矿、渔业和其他领域的核心作用，开发区分不同微生物群的可靠方法非常重要。然而，大多数细菌群目前仅根据它们在 16S rRNA 树中的分支来区分。由于 16S 序列信息本身并不能预测大多数群体的表型性状，因此没有已知群体特异性的分子或生化特性。为了可靠和全面地了解不同微生物群体的生物学特性，识别特定目标群体所独有的进化保守性状至关重要，这些特征可以将它们与所有其他微生物区分开来。基因组序列为发现每个群体特有的新型分子标记提供了独特且明确的资源。利用基因组序列，我的团队率先发现了两种类型的分子标记：保守特征插入缺失 (CSI) 和保守特征蛋白 (CSP)，它们在特定生物体群体中独特存在。由于基因型指定了表型，这些分子标记将为发现每组生物体独特的新生化/生物特性以及开发针对这些生物体的新诊断和治疗方法提供重要手段。未来5年，我们在这一领域的工作将利用基因组序列全面研究三类重要的细菌，即细菌。假单胞菌目、乳酸菌目和芽孢杆菌目。这些群体含有许多“优先人类病原体”、几种主要植物病原体，以及在乳制品和农业行业中发挥关键作用的其他细菌。我们将鉴定这些大群体中不同致病细菌和有益细菌的多种可靠特征，从而为发现这些细菌的新生化特征和改进其鉴定手段提供重要手段。此外，该提案的一个重要目标是测试/建立蛋白质结构中的 CSI 可用于开发新型细胞生长抑制化合物的原理证明。这一概念的建立可以为针对含有 CSI 的生物体的新型药物/抑制剂提供大量资源。总的来说，这里提出的工作应该极大地增进我们对许多重要微生物群的理解，这些发现的应用应该会导致这些细菌造成的健康、农业和经济负担显着减轻。