Studies on Dimorphism in Sporothrix schenckii

申克孢子丝菌二态性的研究

基本信息

批准号：
7501357
负责人：
NURI RODRIGUEZ-DEL VALLE
金额：
$ 29.39万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7501357
关键词：
Acquired Immunodeficiency Syndrome Antifungal Agents Appearance Biochemistry Calcium Calcium Channel Calcium Signaling Calcium ion Cell Cycle Cell Density Cell membrane Cells Characteristics Coupled Cyclic AMP Cyclic Nucleotides Development Disease Disruption Environment Enzymes Eukaryota Eukaryotic Cell Evaluation Event Evolution Future G Protein Gene G-Protein-Coupled Receptors GTP-Binding Proteins Genes Germ Germination Goals Grouping Heterotrimeric G Protein Subunit Heterotrimeric GTP-Binding Proteins Human Individual Kinetics Knock-out Laboratories Lead Membrane Microscopic Molds Morphogenesis Morphology Mycelium Organism Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phorbol Esters Phylogenetic Analysis Physiology Plants Play Polymerase Chain Reaction Process Protein Kinase C Protein Subunits Proteins Rate Role Signal Pathway Signal Transduction Site Sorting - Cell Movement Sporothrix System Temperature Testing Time Tissue-Specific Gene Expression Tube Work Yeasts cell type citrate carrier design dimorphism drug development extracellular fungus immunosuppressed information gathering mutant nuclear division pathogen response size yeast two hybrid system

项目摘要

The development of new drugs for the treatment of fungal diseases is of primary importance. Nevertheless, this will not be achieved until we have a more distinct picture of basic fungal physiology and biochemistry. The study of key enzymes involved in fungal dimorphism will help determine if these enzymes are useful targets for future antifungal drug development and to understand the mechanisms these organisms use to establish themselves in the human host. Even though dimorphism is an important characteristic of most pathogenic fungi, the information concerning the key enzymes involved in the control of this process is incomplete for most fungi. S. schenckii is a unique dimorphic pathogenic fungi. Phylogenetic analysis of S. schenckii genes studied in our laboratory groups this fungus closer to the filamentous fungi rather than to the customary human pathogens. But unlike most of the filamentous fungi, S. schenckii is unique in the sense that it is dimorphic and that at some point in evolution it acquired what was necessary to survive in the human host. Studies done by us revealed that the development of a particular morphology in S. schenckii, depends on transmembrane signaling pathways that respond to cell density, external pH, temperature, extracellular calcium concentration, cyclic nucleotides and protein kinase C (PKC) effectors, such as phorbol esters. Our working hypothesis is that the presence of heterotrimeric G proteins is fundamental in the expression of dimorphism in this fungus and ultimately in its pathogenicity. Heterotrimeric G proteins are important enzymes that transduce signals from the membrane into the cell in eukaryotic systems. The long term experimental objectives of this work are concerned with elucidating the role each G protein subunit plays on the development of alternate morphologies in this fungus. This includes the evaluation of the effects that specific heterotrimeric G protein gene knockouts have on the yeast to mycelium transition and the yeast cell cycle and the identification of the proteins that interact with the various forms of the G protein subunits in order to construct the signal tranduction pathways that are initiated at the cell membrane and ultimately result in differential gene expression and a visible change in morphology; This information will help to elucidate the chain of events that lead to a change in morphology in S. schenckii and the role G proteins have in the dimorphic process, and will ultimately contribute to determine if these enzymes are useful targets for future antifungal drug development.

开发用于治疗真菌疾病的新药至关重要。然而，除非我们对基本真菌生理学和生物化学的更独特的了解，这将无法实现。对二态性涉及的关键酶的研究将有助于确定这些酶是否是未来抗真菌药物开发的有用靶标，并了解这些生物在人类宿主中使用这些生物的机制。即使二态性是大多数致病性真菌的重要特征，但与大多数真菌有关此过程中涉及的关键酶的信息是不完整的。 S. schenckii是一种独特的二态致病真菌。在我们的实验室组中研究的S. schenckii基因的系统发育分析，这种真菌更接近丝状真菌，而不是接近习惯的人类病原体。但是，与大多数丝状真菌不同，S. schenckii是独一无二的，从某种意义上说，它是二态性的，并且在进化中的某个时刻，它获得了在人类宿主中生存的必要物品。我们所做的研究表明，S. schenckii中特定形态的发展取决于跨膜信号传导途径，这些跨膜信号通路对细胞密度，外部pH值，温度，细胞外钙浓度，环核苷酸和蛋白激酶C（PKC）（PKC）的效应（例如phorbol酯）的作用。我们的工作假设是，异三聚体G蛋白的存在对于二态性的表达至关重要真菌，最终在其致病性上。异三聚体G蛋白是重要的酶，可将信号从膜转移到真核系统中的细胞中。这项工作的长期实验目标与阐明了每个G蛋白亚基在这种真菌中替代形态的发展中所起的作用。这包括评估特定异三聚体G蛋白基因基因敲除对酵母到菌丝体过渡和酵母细胞周期的影响，以及与G蛋白亚基相互作用的蛋白质的鉴定，以构建信号曲折途径，以构建在细胞膜上启动的信号曲折途径，并最终导致差异基因的表达和可见的摩擦式变化。该信息将有助于阐明导致S. schenckii形态发生变化的事件链，G蛋白在蛋白质中的作用在双态过程，最终将有助于确定这些酶是否是未来抗真菌药物开发的有用靶标。