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Molecular signaling mechanisms controlling Cryptosporidium proliferation and development

控制隐孢子虫增殖和发育的分子信号机制

基本信息

批准号：
10548206
负责人：
Sumiti Vinayak Alam
金额：
$ 38.45万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548206
关键词：
Biochemical Genetics Biological Biological Assay Biological Models Biological Process Biology Calcium Candidate Disease Gene Cessation of life Child Clustered Regularly Interspaced Short Palindromic Repeats Complex Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Dependence Development Diarrhea Disease Disease Outbreaks Drug Targeting Epithelial Cells Epitopes FDA approved Fertilization Future Gametogenesis Genetic Genome Germ Cells Goals Homologous Gene Human Immunocompromised Host In Vitro Individual Infant Infection Intestines Knowledge Laboratories Life Cycle Stages Light Link Mediating Meiosis Methods Modeling Molecular Molecular Genetics Mus Nature Oocysts Parasite Control Parasites Pharmaceutical Preparations Phenotype Phosphorylation Phosphotransferases Plants Plasmodium Play Proliferating Protein-Serine-Threonine Kinases Recreation Resource-limited setting Role Rotavirus Sexual Development Signal Pathway Signal Transduction Signaling Protein System Technology Testing Toddler Toxoplasma Transgenic Organisms Vaccines Water asexual calcium-dependent protein kinase candidate identification chemical genetics diarrheal disease drug development effective therapy enteric infection genetic approach genetic manipulation genome editing immunological status in vivo insight intestinal epithelium kinase inhibitor male mouse model mutant nitazoxanide novel novel therapeutics novel vaccines parasite genome pathogen prevent programs protein degradation reverse genetics stem superresolution microscopy transmission process vaccine development waterborne outbreak

项目摘要

Project Abstract Cryptosporidium is a leading cause of diarrheal disease (cryptosporidiosis) and death among young children living in resource-poor settings. In the US, Cryptosporidium is the major cause of waterborne outbreaks linked to recreational water use. Currently, there is no fully effective drug and no vaccine to treat or prevent cryptosporidiosis. The only available US FDA approved drug, nitazoxanide has no proven efficacy in young children with weak immune status and immunocompromised individuals. Therefore, there is an urgent need to develop new drugs and vaccine to reduce the burden of cryptosporidiosis. Progress in anti-cryptosporidial drug and vaccine development has been hampered due to our limited understanding of parasite biology. The underlying reasons for this slow progress have been the unavailability of a robust method to continuously propagate Cryptosporidium, and the absence of molecular genetics to manipulate the parasite genome. We have overcome these hurdles by developing a powerful technology to manipulate the Cryptosporidium genome and propagate these genetically modified parasites in an immunocompromised mouse model system. The key advantage of this genetic system is that the entire life cycle of Cryptosporidium (both asexual and sexual stages) is completed in the mouse intestine, allowing us to unravel parasite biology (Vinayak et al 2015, Nature 523:477). We lack an understanding of the molecular signaling mechanisms that control development of parasite stages for successful completion of the complex life cycle. Signaling pathway components such as the plant-like calcium-dependent protein kinases (CDPKs) have emerged as attractive drug targets in Cryptosporidium and related parasites, due to the absence of their homologues in human host. Taking advantage of our genetic system, we have demonstrated the efficacy of selective bumped kinase inhibitors against calcium-dependent protein kinase-1 (CDPK1), thus indicating a critical role of this signaling kinase in C. parvum. Utilizing the conditional protein degradation system recently developed in our laboratory, we have demonstrated the essential role of CDPK1 in asexual proliferation and parasite survival. Moreover, we have compelling preliminary evidence that sheds light on the role of two signaling kinases in sexual developmental stages. The goal of this project is to elucidate the mechanistic role of these signaling proteins in regulating development of asexual and sexual stages in C. parvum required for parasite proliferation and transmission. Elucidation of these mechanisms will provide novel insights into the fundamental biology of Cryptosporidium, and open new avenues for development of effective therapies.

项目摘要