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Systematic in vitro and in vivo genetic analysis of C.albicans protein kinases

白色念珠菌蛋白激酶的系统体外和体内遗传分析

基本信息

批准号：
10308519
负责人：
Damian J Krysan
金额：
$ 19.19万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308519
关键词：
Address Affect Age Antifungal Agents Bar Codes Biological Assay CRISPR/Cas technology Candida albicans Candidiasis Cell surface Cells Collection Communities Complex Development Disease Disseminated candidiasis Drug Targeting Environment Eye Gastrointestinal tract structure Genetic Genetic Transcription Goals Heart Human Hyphae In Vitro Infection Kidney Knowledge Libraries Life Liver Mediating Microbial Biofilms Modeling Mucous Membrane Neuraxis Organ Pathogenesis Pathway Analysis Pathway interactions Persons Phosphoproteins Physiological Physiology Process Protein Analysis Protein Dynamics Protein Kinase Research Resources Role Skin Spleen System Therapeutic Virulence Yeast Model System base body system design experimental study fitness genetic analysis genetic resource gut colonization human pathogen in vivo inorganic phosphate irritation microbiota mouse model mutant novel strategies novel therapeutic intervention novel therapeutics pathogen pathogenic fungus programs transcription factor urogenital tract

项目摘要

PROJECT SUMMARY Candida albicans is both a commensal component of the normal human microbial flora and an important human pathogen. Although the commensal niches occupied by C. albicans are primarily limited to the gastrointestinal and genitourinary tracts, candidal disease, in contrast, can involve a wide range of organ systems including kidney, spleen, liver, heart, eye, the central nervous system, and skin/mucosae. As such, C. albicans is a versatile pathogen that adapts to a wide range of physiologically diverse environments within the human host. Understanding the systems that facilitate this adaptation is central to developing detailed mechanistic models of C. albicans pathogenesis and could inform the identification of new therapeutic approaches to candidiasis. To date, C. albicans transcription factors (TF) are the best characterized components of this system, due in part to the availability of comprehensive sets of TF deletion mutants. In contrast, upstream regulators of C. albicans physiology such as protein kinases (PK) have not been systematically studied to the same extent. To address this knowledge gap, the long-term goal of our project is to systematically characterize the role of PKs in C. albicans pathobiology. As a first step toward this goal, we propose to: 1) generate and validate a barcoded set of homozygous and heterozygous C. albicans PK deletion mutants using a transient CRISPR/Cas9 strategy; 2) Systematically characterize the PK deletion mutants in two murine model of candidiasis and two virulence relevant in vitro processes: biofilm and hyphae formation; 3) Identify and characterize the network of PK-TF pairs that regulate biofilm and hyphae formation using genetic interaction analysis. Successful completion of these aims will provide a useful genetic resource for the research community, provide the first systematic functional characterization of C. albicans PKs in vivo and in vitro, and set the stage for subsequent in-depth analyses of the genetic networks regulated by C. albicans PKs.

项目总结