Mechanisms of IL-17 Mediated Host Defense in the Kidney
IL-17 介导的肾脏宿主防御机制
基本信息
- 批准号:9023669
- 负责人:
- 金额:$ 30.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-20 至 2020-06-30
- 项目状态:已结题
- 来源:
- 关键词:A MouseAbdomenAcuteAdultAgonistAngiotensin-Converting Enzyme InhibitorsAnimal ModelAntifungal AgentsApplications GrantsBiochemicalBlood PressureBradykininBradykinin ReceptorCandidaCandida albicansCandidiasisCatheterizationCellsCessation of lifeChromatinChronicCleaved cellClinicalClinical TrialsDataDiagnosisDiseaseDisseminated candidiasisDistalDrug TargetingDrug resistanceEpithelial CellsEquilibriumExperimental ModelsFDA approvedFibrosisGene ExpressionGene TargetingGoalsHematopoietic Stem Cell TransplantationHost DefenseHost Defense MechanismHumanHyphaeImmune systemImmunityIndwelling CatheterInfectionInflammationInjuryInterleukin-17InterventionInvadedKallikrein-Kinin SystemKidneyKidney DiseasesKidney FailureKininogenaseKininogensKnowledgeLifeLinkLiverMalignant NeoplasmsMediatingMediator of activation proteinModalityMorbidity - disease rateMouse StrainsMucous MembraneMusNosocomial InfectionsOperative Surgical ProceduresOral cavityOrganOxidation-ReductionPathogenesisPathologyPathway interactionsPatientsPremature BirthRNA InterferenceRegulationRenal functionReportingResearchResistanceRoleSeriesSerine ProteaseSignal PathwaySignal TransductionSolidSterilitySystemSystemic diseaseTherapeuticTherapeutic immunosuppressionTissuesTreatment EfficacyTubular formationUrinary KallikreinVaccinescandidemiacell typecombatcytokineeffective therapyfungusin vivoinhibitor/antagonistinsightkidney cellmortalitymouse modelneonatenew therapeutic targetnovelnovel therapeuticsoverexpressionpre-clinicalpreclinical studyprophylacticpublic health relevancereceptorresponsevaccine development
项目摘要
DESCRIPTION (provided by applicant): Candida albicans is a commensal fungus that resides in the oral cavity and gut mucosa. Normally, healthy humans efficiently control the colonization of Candida. However, in certain conditions such as solid organ and hematopoietic stem cell transplantation, receipt of immunosuppressive therapy, cancer, premature birth or indwelling catheterization, Candida albicans can disseminate and cause life-threatening systemic disease. In fact, disseminated candidiasis is the 4th most common nosocomial infection, with fatality rates up to 40-60%. The lack of effective vaccines and development of drug resistance act as major constraints in successfully treating these patients. Therefore, there is a serious unmet clinical need to develop better therapeutic and prophylactic strategies to combat these fatal infections. During disseminated infection, Candida hyphae invade target organs, particularly kidney and liver. Death from candidemia results from renal insufficiency in a substantial number of patients. While the contribution of mucosal immune system in anti-Candida host defense has been well studied in recent years, the role of local immunity in target organs, particularly the kidney, is largely overlooked. The cytokine IL-17 has emerged as a key mediator of host defense against Candida species. Both humans and experimental mouse models deficient in IL-17 pathways such as the IL-17 receptor A (IL-17RA) are susceptible to disseminated candidiasis. Our preliminary data show that IL-17RA signaling in non-hematopoietic cells is required for renal defense against systemic Candida infection. Nevertheless, the underlying mechanisms of IL-17-mediated host defense against systemic candidiasis particularly in the kidney are not known. Interestingly, we have discovered an unexpected role for IL-17 in inducing the Kallikrein-Kinin System (KKS) in kidney following candidemia. We also show that overexpression of Klk1 protects IL-17RA-/- mice from candidemia. Kallikreins are serine proteases that cleave kininogens to form bradykinin. The KKS system is known to be involved in renal protection against both acute and chronic kidney injury, but almost no connections of the KKS to candidiasis have been previously reported. The overall goal of this grant application is to determine the underlying mechanisms of IL-17-Klk1 mediated immunity during systemic candidiasis and ultimately to exploit this knowledge for therapeutic benefit. To that end, we will use a series of renal cell type specific gene-targeted mice, global Klk1 and bradykinin receptor-deficient mice and bradykinin receptor agonists to define mechanisms of IL-17-driven renal protection against candidemia (Aim 1). Knowledge gained from these studies will be used in pre-clinical studies to evaluate the therapeutic efficacy of targeting IL-17- KKS axis in kidney specific anti-fungal immunity (Aim 2). Our long term goal is to reduce the morbidity and mortality associated with this devastating hospital acquired infection.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Partha Sarathi Biswas其他文献
Correction: Genomic prediction and QTL analysis for grain Zn content and yield in Aus-derived rice populations
- DOI:
10.1007/s13562-025-00983-8 - 发表时间:
2025-04-28 - 期刊:
- 影响因子:1.500
- 作者:
Tapas Kumer Hore;C. H. Balachiranjeevi;Mary Ann Inabangan-Asilo;C. A. Deepak;Alvin D. Palanog;Jose E. Hernandez;Glenn B. Gregorio;Teresita U. Dalisay;Maria Genaleen Q. Diaz;Roberto Fritsche Neto;Md. Abdul Kader;Partha Sarathi Biswas;B. P. Mallikarjuna Swamy - 通讯作者:
B. P. Mallikarjuna Swamy
Partha Sarathi Biswas的其他文献
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{{ truncateString('Partha Sarathi Biswas', 18)}}的其他基金
RNA binding proteins in end-organ autoimmune pathology
终末器官自身免疫病理学中的 RNA 结合蛋白
- 批准号:
10569112 - 财政年份:2022
- 资助金额:
$ 30.67万 - 项目类别:
RNA binding proteins in end-organ autoimmune pathology
终末器官自身免疫病理学中的 RNA 结合蛋白
- 批准号:
10450945 - 财政年份:2022
- 资助金额:
$ 30.67万 - 项目类别:
Mechanisms of renal protection against disseminated candidiasis
抵抗播散性念珠菌病的肾脏保护机制
- 批准号:
10376250 - 财政年份:2021
- 资助金额:
$ 30.67万 - 项目类别:
Mechanisms of renal protection against disseminated candidiasis
抵抗播散性念珠菌病的肾脏保护机制
- 批准号:
10190010 - 财政年份:2021
- 资助金额:
$ 30.67万 - 项目类别:
Mechanisms of neutrophil dysfunction in antifungal immunity
中性粒细胞功能障碍在抗真菌免疫中的机制
- 批准号:
10454893 - 财政年份:2019
- 资助金额:
$ 30.67万 - 项目类别:
Mechanisms of neutrophil dysfunction in antifungal immunity
中性粒细胞功能障碍在抗真菌免疫中的机制
- 批准号:
9815169 - 财政年份:2019
- 资助金额:
$ 30.67万 - 项目类别:
Mechanisms of neutrophil dysfunction in antifungal immunity
中性粒细胞功能障碍在抗真菌免疫中的机制
- 批准号:
10223106 - 财政年份:2019
- 资助金额:
$ 30.67万 - 项目类别:
Mechanisms of neutrophil dysfunction in antifungal immunity
中性粒细胞功能障碍在抗真菌免疫中的机制
- 批准号:
10673766 - 财政年份:2019
- 资助金额:
$ 30.67万 - 项目类别:
Regulation of IL-17 signaling by RNA binding proteins in kidney diseases
RNA 结合蛋白在肾脏疾病中调节 IL-17 信号传导
- 批准号:
9762270 - 财政年份:2019
- 资助金额:
$ 30.67万 - 项目类别:
Mechanisms of IL-17 Mediated Host Defense in the Kidney
IL-17 介导的肾脏宿主防御机制
- 批准号:
9144776 - 财政年份:2015
- 资助金额:
$ 30.67万 - 项目类别:
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