Complement as a modulator of immunosuppression and progression in Polycystic Kidney Disease
补体作为多囊肾病免疫抑制和进展的调节剂
基本信息
- 批准号:10459557
- 负责人:
- 金额:$ 11.66万
- 依托单位:
- 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:2021-08-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adaptive Immune SystemAnaphylatoxinsAutomobile DrivingAutosomal Dominant Polycystic KidneyBindingC3AR1 geneC5a anaphylatoxin receptorCD8-Positive T-LymphocytesCancer ModelCell SeparationCellsClinical TrialsComplementComplement 3aComplement 5aComplement ActivationComplement InactivatorsComplement Membrane Attack ComplexCystCyst FluidCystic kidneyDNA Sequence AlterationDataDiseaseDisease modelEnd stage renal failureEpithelialEpithelial CellsFDA approvedFlow CytometryFutureGeneticGoalsGrantGrowthImageImmuneImmune EvasionImmune checkpoint inhibitorImmunityImmunosuppressionImmunotherapyImpairmentInheritedInnate Immune SystemInvestigationK-Series Research Career ProgramsKidneyKidney DiseasesLeadMalignant NeoplasmsMediatingMetabolicMethodsModelingMolecularMusNational Institute of Diabetes and Digestive and Kidney DiseasesOutcomePathologyPathway interactionsPatientsPharmaceutical PreparationsPhenotypePolycystic Kidney DiseasesPre-Clinical ModelProductionProteinsPublicationsPublishingQuality of lifeReceptor InhibitionRegimenRegulatory T-LymphocyteReportingResearchResearch PersonnelRoleSeriesSeveritiesSeverity of illnessShapesSignal TransductionT-LymphocyteTestingTherapeuticTimeTranslatingTumor BurdenTumor EscapeTumor-associated macrophagesUp-RegulationWorkadaptive immunitycancer immunotherapycell typeclinically relevantcomplement pathwaycytokinefluorophoreimmune checkpointinhibitorinnovationmacrophagemouse modelnew therapeutic targetoverexpressionpre-clinicalpre-clinical researchreceptortherapeutic evaluationtherapeutic targettranslational research programtumor progressiontumor-immune system interactions
项目摘要
PROJECT SUMMARY
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common, monoallelic nephropathy
worldwide, characterized by continuous renal cysts growth leading to end stage kidney disease. A single FDA
approved therapy is available, but it merely slows cyst growth and impacts quality of life, highlighting the urgent
need for new treatment options. ADPKD presents with high phenotypic variability, suggesting that mechanisms
beyond the genetic mutation to either PKD1 or PKD2 influence disease severity. Recent data have implicated
immune cells as modulators of disease severity. Multiple publications highlight that M2-like renal macrophages
promote cystic progression. Conversely, data from my K01, using the slowly progressive, orthologous Pkd1
p.R3277C (Pkd1RC/RC) ADPKD model, show that CD8+ T cells can inhibit renal cyst growth. We further found that
the renal cystic microenvironment displays multiple features of immunosuppression such as increased numbers
of CD4+ regulatory T cells, metabolic reprogramming, and engagement of immune checkpoints. Indeed, immune
checkpoint inhibitors, which lead to reactivation of CD8+ T cells, alleviate cystic disease in the Pkd1RC/RC model.
What remains unknown are the mechanisms that drive immunosuppression, which may present important/novel
therapeutic targets. In cancer, a disease that parallels PKD at the cellular and molecular level, activation of the
complement pathway has been shown to promote an immunosuppressive microenvironment. The complement
cascade is a central part of the innate immune system that regulates adaptive immunity. Complement has been
shown to be upregulated in PKD cells, patient kidneys/cyst fluid, and murine models, including the Pkd1RC/RC
mouse as shown by our preliminary data. Further, genetic loss or non-selective inhibition of the complement
protein C3 slows cyst growth in murine PKD models. We hypothesize that complement signaling drives PKD, in
part, by creating an immunosuppressive microenvironment which impairs the adaptive immune system to halt
cyst growth. This project has two aims. In Aim 1, we will utilize fluorescent-activated cell sorting, flow cytometry,
and multispectral immunofluorescent imaging to determine which cells are key producers and responders of
complement signaling in the Pkd1RC/RC kidney. We will further correlate these findings to disease severity. In Aim
2, we will test if targeted complement inhibition alleviates cystic disease. This will be the first of such studies
using a clinically relevant, specific complement inhibitor in a model orthologous to ADPKD, the Pkd1RC/RC mouse.
We will further utilize sophisticated 64-fluorophore capable flow cytometry methods to investigate how
complement inhibition alters the cystic immune microenvironment with specific focus on immunosuppressive
features. These investigations directly expand upon my NIDDK K01 work and will provide key preliminary data
for a competitive R01 application. Obtaining this R03 will further facilitate my transition into an independent
investigator with an innovative, preclinical, and translational research program that focuses on the role of the
cystic microenvironment as modulator of and therapeutic target for PKD.
项目总结
项目成果
期刊论文数量(0)
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Katharina Hopp其他文献
Katharina Hopp的其他文献
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{{ truncateString('Katharina Hopp', 18)}}的其他基金
Complement as a modulator of immunosuppression and progression in Polycystic Kidney Disease
补体作为多囊肾病免疫抑制和进展的调节剂
- 批准号:
10282996 - 财政年份:2021
- 资助金额:
$ 11.66万 - 项目类别:
Defining the functional role of T-cells in Autosomal Dominant Polycystic Kidney Disease pathology
定义 T 细胞在常染色体显性多囊肾病理学中的功能作用
- 批准号:
10224881 - 财政年份:2018
- 资助金额:
$ 11.66万 - 项目类别:
Defining the functional role of T-cells in Autosomal Dominant Polycystic Kidney Disease pathology
定义 T 细胞在常染色体显性多囊肾病理学中的功能作用
- 批准号:
10457284 - 财政年份:2018
- 资助金额:
$ 11.66万 - 项目类别:
Defining the functional role of T-cells in Autosomal Dominant Polycystic Kidney Disease pathology
定义 T 细胞在常染色体显性多囊肾病理学中的功能作用
- 批准号:
10323797 - 财政年份:2018
- 资助金额:
$ 11.66万 - 项目类别:
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