Role of intracellular complement activation in kidney fibrosis
细胞内补体激活在肾纤维化中的作用
基本信息
- 批准号:10264916
- 负责人:
- 金额:$ 24.23万
- 依托单位:
- 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:2020-09-19 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAtlasesC3AR1 geneCell SurvivalCell physiologyCellsChronic Kidney FailureCicatrixClinicalClinical TrialsComplementComplement 5aComplement ActivationDataData SetDiseaseEnd stage renal failureEngineeringEpithelial CellsFibrosisGeneticHealthInflammatoryInjuryInjury to KidneyInvadedKidneyKidney DiseasesLigandsMetabolismMorbidity - disease rateMusMyeloid CellsNatural ImmunityNuclear RNAPathogenesisPathologicPathway interactionsPericytesPharmaceutical PreparationsPhenotypePhysiologyPlayPopulationPrevalenceProcessProteomicsReagentRenal functionRiskRoleSignal TransductionSystemT-LymphocyteTestingTherapeuticTubular formationUnited Statesadaptive immunityaging populationautocrinecell typecomplement systemcostglomerulosclerosiskidney cellkidney fibrosiskidney repairmacrophagemortalitymouse modelnephrogenesisparacrinepathogenreceptorrecruitrenal scarringtranscriptome sequencing
项目摘要
PROJECT SUMMARY / ABSTRACT
The prevalence of Chronic Kidney Disease (CKD) in the US is high and continues to rise in our aging population.
Independent of the cause of CKD, tubulointerstitial fibrosis and glomerulosclerosis represent major pathways of
progression of kidney disease, however, there are no approved drugs to treat kidney fibrosis that could
ameliorate progression of CKD. In recent studies we demonstrated that locally synthesized and activated kidney
complement components drive the pathogenesis of kidney fibrosis. The complement system is of major
importance in innate and adaptive immunity, but dysregulated complement has been shown to play a major role
in kidney injury. Our pilot data, leveraging single nuclear RNA sequencing (snRNAseq), indicate cell-specific
compartmentation of complement components, particularly of C3 and C5 in RTE cells. Our data also indicate
that these components ligand their cognate receptors, C3aR and C5aR1, on kidney macrophages in murine
models of kidney fibrosis. In preliminary datasets, genetic deletion of these factors in a cell-specific manner
imparted significant protection against renal scarring. Thus, the central hypothesis to be tested in this application
is that intrinsic expression of complement components from kidney cells, their processing to active fragments
and activation of their cognate receptors are key to the progressive loss of kidney function and scaring. This
hypothesis will be investigated via the following independent, but complementary, specific aims: Aim 1: Delineate
the intracellular expression of complement components by kidney cells. We will use snRNAseq in murine kidney
fibrosis to delineate cell type-specific expression of complement components and their receptors. We will confirm
data by proteomic approaches and identify the processing machinery generating active secretory fragments from
complement components. Aim 2. Determine the importance of RTE-derived C3 for renal physiology and fibrosis.
We will use mice engineered to lack C3 specifically in RTE cells to determine the relevance of intracellular
complement for renal physiology and injury-induced fibrosis. We will study mice lacking the C3ar1 receptor on
either kidney or myeloid cells to establish whether there is an obligate requirement for autocrine or paracrine C3
signaling. Aim 3. Determine the impact of C5a/C5aR1 axis activation on macrophages for the induction of kidney
fibrosis or repair. We will validate our preliminary observations that macrophage-specific deletion of C5ar1
reduces fibrosis. We will determine whether C5ar1 directly affects macrophage phenotype and function, or
whether C5ar1 macrophages promote scarring by recruiting and activating inflammatory T cells. Collectively,
this proposal will establish a comprehensive atlas of complement component expression in kidney cells in healthy
and injured kidneys, establish key mechanisms of these pathways in kidney scarring and enable clinical targeting
of these pathways with therapeutically relevant strategies.
项目总结/摘要
美国慢性肾脏病(CKD)的患病率很高,并且在我们的老龄化人口中继续上升。
与CKD的病因无关,肾小管间质纤维化和肾小球硬化是CKD的主要途径。
然而,由于肾脏疾病的进展,没有批准的药物可以治疗肾脏纤维化,
改善CKD的进展。在最近的研究中,我们证明了局部合成和激活的肾脏
补体成分驱动肾纤维化的发病机制。补体系统主要
在先天性和适应性免疫中重要性,但失调的补体已被证明起主要作用
肾脏损伤我们的试验数据,利用单核RNA测序(snRNAseq),表明细胞特异性
补体成分的区室化,特别是RTE细胞中的C3和C5。我们的数据还表明
这些成分配体的同源受体,C3 aR和C5 aR 1,在小鼠肾巨噬细胞,
肾纤维化模型。在初步数据集中,这些因子以细胞特异性方式的遗传缺失
对肾瘢痕形成有显著的保护作用。因此,在本申请中待检验的中心假设
是来自肾细胞补体成分的内在表达,它们加工成活性片段
其同源受体的激活是肾功能进行性丧失和瘢痕形成的关键。这
将通过以下独立但互补的具体目标对假设进行研究:目标1:
肾细胞补体成分的细胞内表达。我们将在小鼠肾脏中使用snRNAseq
纤维化以描绘补体成分及其受体的细胞类型特异性表达。我们将确认
数据通过蛋白质组学的方法,并确定产生活性分泌片段的加工机制,
互补成分目标二。确定RTE衍生的C3对肾脏生理学和纤维化的重要性。
我们将使用在RTE细胞中特异性缺乏C3的小鼠来确定细胞内C3的相关性。
补充肾脏生理和损伤诱导的纤维化。我们将研究缺乏C3 ar 1受体的小鼠,
肾脏或骨髓细胞,以确定是否存在自分泌或旁分泌C3的专性需求
发信号。目标3.确定C5 a/C5 aR 1轴激活对巨噬细胞诱导肾
纤维化或修复。我们将验证我们的初步观察,巨噬细胞特异性C5 ar 1缺失
减少纤维化。我们将确定C5 ar 1是否直接影响巨噬细胞的表型和功能,
C5 ar 1巨噬细胞是否通过募集和激活炎性T细胞促进瘢痕形成。总的来说,
该建议将建立健康人肾细胞中补体成分表达的综合图谱,
和损伤的肾脏,建立这些途径在肾瘢痕形成中的关键机制,并使临床靶向
这些途径的治疗相关策略。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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DIDIER PORTILLA其他文献
DIDIER PORTILLA的其他文献
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{{ truncateString('DIDIER PORTILLA', 18)}}的其他基金
Role of intracellular complement activation in kidney fibrosis
细胞内补体激活在肾纤维化中的作用
- 批准号:
10461113 - 财政年份:2020
- 资助金额:
$ 24.23万 - 项目类别:
Role of intracellular complement activation in kidney fibrosis
细胞内补体激活在肾纤维化中的作用
- 批准号:
10121560 - 财政年份:2020
- 资助金额:
$ 24.23万 - 项目类别:
Role of apolipoprotein M in acute kidney injury
载脂蛋白M在急性肾损伤中的作用
- 批准号:
7782702 - 财政年份:2009
- 资助金额:
$ 24.23万 - 项目类别:
Role of apolipoprotein M in acute kidney injury
载脂蛋白M在急性肾损伤中的作用
- 批准号:
8195623 - 财政年份:2009
- 资助金额:
$ 24.23万 - 项目类别:
Role of apolipoprotein M in acute kidney injury
载脂蛋白M在急性肾损伤中的作用
- 批准号:
7690144 - 财政年份:2009
- 资助金额:
$ 24.23万 - 项目类别:
Role of apolipoprotein M in acute kidney injury
载脂蛋白M在急性肾损伤中的作用
- 批准号:
8262618 - 财政年份:2009
- 资助金额:
$ 24.23万 - 项目类别:
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