Role of Host Protein Kinase C in Cryptosporidiosis

宿主蛋白激酶 C 在隐孢子虫病中的作用

基本信息

批准号：
10443895
负责人：
Chelsea S. Marie
金额：
$ 70.16万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2020-08-20 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443895
关键词：
Address Age Age of Onset Area Bangladesh Bioinformatics Biology Birth Cells Cellular biology Child Chromosome Positioning Clinical Collaborations Color Communicable Diseases Country Cryptosporidiosis Cryptosporidium Data Development Diarrhea Disease Disease susceptibility Dominant-Negative Mutation Drug Targeting Entamoeba Environment Epithelial Cells FDA approved Future Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Screening Genome Scan Genotype Health Human Human Genetics Immune Immunocompromised Host In Vitro Infant Infection Integration Host Factors International Intestines Introns Invaded Investigational New Drug Application Knowledge Life Linkage Disequilibrium Mediator of activation protein Molecular Biology Mus Outcome PRKCA gene Parasites Parasitic infection Pathogenesis Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenotype Predisposition Protein Analysis Protein Isoforms Protein Kinase Protein Kinase C Protein Kinase C Inhibitor Publications Research Personnel Resistance Resources Risk Role Severities Single Nucleotide Polymorphism Sporozoites Susceptibility Gene Testing Time Universities Untranslated RNA Vaccines Validation Variant Virginia Work adaptive immune response antagonist base causal variant cell killing clinically relevant cohort collaborative environment drug development effective therapy emerging antimicrobial resistance experience field study genetic variant genome wide association study genome-wide global health improved in vivo in vivo Model inhibitor innovation intestinal epithelium low and middle-income countries microorganism mouse model multidisciplinary novel parasite invasion pathogen pediatric patients prevent programs skills targeted sequencing targeted treatment therapeutic target vaccine development

项目摘要

PROJECT SUMMARY Impact: This proposal addresses the pressing need for effective treatments for cryptosporidiosis in infants. The therapeutic target is human protein kinase C (PKCα), which we recently discovered as a host susceptibility gene for cryptosporidiosis. Successful completion of this work will broadly advance the field of host-targeted therapy by taking a hit from a forward-genetic screen through mechanistic validation during disease. Significance: Cryptosporidiosis is one of the top 5 causes of diarrhea in children in low- and middle-income countries. There is no vaccine and the drugs are extremely limited with none approved for infants. Thus, there is an urgent need for effective therapies, particularly for children. This proposal sets a precedent for developing host targets for microorganisms, an area of high significance in the face of emerging antimicrobial resistance. Innovation: A genome-wide scan for infectious disease susceptibility in infants from low-resource countries had never been done until it was pioneered by our investigator team. The proposal integrates human genetics and parasite cell biology to develop the discovery of PKCα into a target for host directed therapy. Our previous work identified novel host factors that could be blocked to prevent cell-killing by Entamoeba parasites. We propose to expand this innovative approach to Cryptosporidium. This strategy is fundamentally different from traditional parasite-targeted drugs and is based on preliminary data that PKCα is a novel host susceptibility factor for cryptosporidiosis. Approach: We have discovered that human PKCα is a key component of susceptibility to cryptosporidiosis in infants using a genome wide scan for disease-associated loci. We hypothesize that PKCα is required for intracellular infection by Cryptosporidium and could be targeted to cure cryptosporidiosis. We will define the role of PKCα in a multi-disciplinary study that integrates an analysis of PKCα during natural infection in infants (Aim 1), targeted sequencing of the PKCα locus to identify the causal SNPs and mechanism of action (Aim 2), and an analysis of host PKCα during in vitro and in vivo infection studies in combination with testing of FDA- approved PKCα antagonists (Aim 3). Successful completion of this R01 will result in an Investigational New Drug Application for a host-targeted PKC drug for cryptosporidiosis. Environment: The Investigators bring strong and complementary skills to accomplish this work. Dr. Marie (PI) is an expert in host and parasite cell and molecular biology. Dr. Duggal leads an internationally regarded program in human genetic susceptibility to infection and Dr. Haque brings extensive experience in field studies in children in Bangladesh. Importantly this team is highly collaborative as evidenced by their past discoveries and co- publications. The team brings together three internationally recognized global health centers: The University of Virginia (Dr. Marie), the ICDDR,B (Dr. Haque), and John Hopkins University (Dr. Duggal). This collaboration will occur in an exciting and rigorous interdisciplinary environment.

项目摘要影响：该提案涉及对婴儿隐孢子虫病有效治疗的迫切需求。治疗靶标是人蛋白激酶C（PKCα），我们最近发现它是宿主易感基因用于隐孢子虫病。这项工作的成功完成将广泛推进宿主目标疗法的领域通过在疾病期间通过机械验证从前遗传筛查中受到打击。意义：隐孢子虫病是低收入和中等收入儿童腹泻的前5个原因之一国家。没有疫苗，这些药物受婴儿的批准非常有限。那，那里迫切需要有效的疗法，特别是对于儿童。该提案为开发的先例树立了先例微生物的宿主靶标，面对新兴的抗菌耐药性，这是一个高显着性的区域。创新：针对低资源国家婴儿传染病易感性的全基因组扫描直到我们的调查员团队率先启动它。该提案整合了人类遗传学和寄生虫细胞生物学将PKCα的发现发展为宿主有向治疗的靶标。我们以前的工作确定的新型宿主因子可能会阻止，以防止肠寄生虫杀死细胞。我们建议将这种创新的方法扩展到隐孢子虫。该策略与传统根本不同以寄生虫为目标的药物，基于初步数据，即PKCα是一种新型的宿主易感因子隐孢子虫病。方法：我们发现人PKCα是对隐孢子虫病易感性的关键组成部分使用基因组广泛扫描进行疾病相关的基因座的婴儿。我们假设PKCα是必需的隐孢子虫细胞内感染，可以靶向治愈隐孢子虫病。我们将定义角色 PKCα的多学科研究，该研究整合了婴儿自然感染期间PKCα的分析（AIM 1），PKCα基因座的靶向测序以识别因果SNP和作用机理（AIM 2），以及在体外和体内感染研究期间对宿主PKCα的分析，并结合了FDA-的测试批准的PKCα拮抗剂（AIM 3）。成功完成此R01将导致研究新的药物用于靶向宿主的PKC药物用于隐孢子虫病。环境：调查人员带来了强大而互补的技能来完成这项工作。玛丽博士（PI）是宿主和寄生虫细胞和分子生物学的专家。 Duggal博士领导了一项国际考虑的计划在人类对感染的遗传敏感性和哈克博士在儿童的现场研究方面具有丰富的经验在孟加拉国。重要的是，这支团队是高度合作的，因为他们过去的发现和共同的共同努力证明了这一点出版物。该团队汇集了三个国际认可的全球卫生中心：弗吉尼亚（Marie博士），ICDDR，B（Haque博士）和John Hopkins University（Duggal博士）。这项合作将发生在令人兴奋而严格的跨学科环境中。