Kidney Aging Impairs Progenitor and Endocrine Function
肾脏老化损害祖细胞和内分泌功能
基本信息
- 批准号:10341118
- 负责人:
- 金额:$ 61.83万
- 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:2020-02-11 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAgeAgingAntibodiesAntioxidantsApoptosisAttentionBiogenesisBiologyCDKN2A geneCell CycleCell physiologyCellsChronicComplementCountryCultured CellsDNA DamageDataDialysis procedureDiseaseDisease OutcomeElderlyEnalaprilEndocrineEpithelial CellsErythrocytesEventExperimental ModelsFRAP1 geneFemaleFocal Segmental GlomerulosclerosisGenesGoalsGrantImpairmentIn VitroInflammationInflammatoryInjuryInjury to KidneyKidneyKidney DiseasesKnowledgeLabelLeadLosartanLoxP-flanked alleleMessenger RNAMitochondriaMusNatural regenerationParietalPericytesPhenotypePlasmaPopulationProcessProductionProteinsPublishingRNAReactive Oxygen SpeciesRenal glomerular diseaseReninReporterReportingRoleStimulusTestingTimeTransgenic Miceage relatedagedaging populationcell agecell regenerationclinically relevantcomplement systemcytokinedensitydesignhealthy agingimprovedin vivoinnovationkidney cellmalemesangial cellnephrogenesisolder patientpatient populationpodocytepreventprogenitorrecruitrepairedresponsesenescencestem cell functionstem cellstranscriptometranscriptome sequencingtranscriptomics
项目摘要
Project Summary and Abstract
Because the US population is living longer, the impact of advanced age on the kidney is highly clinically
relevant. Kidney disease outcomes are worse in the older versus younger patient population s and the elderly
comprise the largest group to initiate dialysis annually in the US. Recent attention in the aged kidney has been
given to cells of renin lineage because of their two essential functions: their endocrine function of producing the
body's supply of renin, and their adult progenitor function as facultative stem cells that transdifferentiate into
cell fates that they partially or fully replace, including podocytes. The scope of the problem is that in addition to
a decrease in total CoRL density in the aged kidney, both functions are also impaired with advancing age.
From the standpoint of glomerular diseases typified by podocyte depletion, reduced CoRL progenitor function
limits podocyte regeneration, and therefore repair in the aged kidney. We reported that aged CoRL undergo
senescence, apoptosis, and DNA damage, with an increase in complement components and inflammatory
cytokines, consistent with a chronic low-grade inflammatory state. Aged CoRL mitochondria have lower
biogenesis and energy, but increased reactive oxygen species accumulation. The knowledge gap is identifying
the mechanisms that cause these changes to CoRL in aged kidneys. Importantly, our data shows that
superimposed glomerular disease compounds the aging phenotype as follows: when podocytes are depleted
in young mice in experimental FSGS, the changes to the transcriptome in young CoRL are very similar to the
changes in CoRL in the healthy aged kidney without disease. We propose that changes to CoRL in glomerular
disease recapitulates and superimposes changes to CoRL in aged kidneys, and that this compounding effect
worsens disease outcomes in aged populations. The unmet need is targeting the mechanisms that impair
CoRL function in the aged kidney with disease, with the ultimate goal to minimize further injury to the aged
kidney. To achieve this, the following specific aims are proposed: (1) Test the hypothesis that senescence
impairs the facultative stem cell function of cells of renin lineage (CoRL) during aging. (2) Test the hypothesis
that chronic inflammation reduces the endocrine phenotype and function of aged cells of renin lineage. (3) Test
the hypothesis that mitochondrial changes in the aged kidney lowers the number of cells of renin lineage.
The significance of these studies includes uncovering, for the first time, potential mechanisms whereby age
impairs the CoRL endocrine phenotype and function, reduces CoRL progenitor function and lowers CoRL
density. In doing so, we will identify targets to modify in disease states in the aged kidney that maintain the
CoRL phenotype and enhance their functions. Innovations include identifying changes to a kidney cell (cells of
renin lineage) following injury to another kidney cell (podocyte loss) in FSGS that recapitulate the aged
phenotype, and that these superimposed changes are very detrimental to the aged kidney.
Project Summary and Abstract
Because the US population is living longer, the impact of advanced age on the kidney is highly clinically
relevant. Kidney disease outcomes are worse in the older versus younger patient population s and the elderly
comprise the largest group to initiate dialysis annually in the US. Recent attention in the aged kidney has been
given to cells of renin lineage because of their two essential functions: their endocrine function of producing the
body's supply of renin, and their adult progenitor function as facultative stem cells that transdifferentiate into
cell fates that they partially or fully replace, including podocytes. The scope of the problem is that in addition to
a decrease in total CoRL density in the aged kidney, both functions are also impaired with advancing age.
From the standpoint of glomerular diseases typified by podocyte depletion, reduced CoRL progenitor function
limits podocyte regeneration, and therefore repair in the aged kidney. We reported that aged CoRL undergo
senescence, apoptosis, and DNA damage, with an increase in complement components and inflammatory
cytokines, consistent with a chronic low-grade inflammatory state. Aged CoRL mitochondria have lower
biogenesis and energy, but increased reactive oxygen species accumulation. The knowledge gap is identifying
the mechanisms that cause these changes to CoRL in aged kidneys. Importantly, our data shows that
superimposed glomerular disease compounds the aging phenotype as follows: when podocytes are depleted
in young mice in experimental FSGS, the changes to the transcriptome in young CoRL are very similar to the
changes in CoRL in the healthy aged kidney without disease. We propose that changes to CoRL in glomerular
disease recapitulates and superimposes changes to CoRL in aged kidneys, and that this compounding effect
worsens disease outcomes in aged populations. The unmet need is targeting the mechanisms that impair
CoRL function in the aged kidney with disease, with the ultimate goal to minimize further injury to the aged
kidney. To achieve this, the following specific aims are proposed: (1) Test the hypothesis that senescence
impairs the facultative stem cell function of cells of renin lineage (CoRL) during aging. (2) Test the hypothesis
that chronic inflammation reduces the endocrine phenotype and function of aged cells of renin lineage. (3) Test
the hypothesis that mitochondrial changes in the aged kidney lowers the number of cells of renin lineage.
The significance of these studies includes uncovering, for the first time, potential mechanisms whereby age
impairs the CoRL endocrine phenotype and function, reduces CoRL progenitor function and lowers CoRL
density. In doing so, we will identify targets to modify in disease states in the aged kidney that maintain the
CoRL phenotype and enhance their functions. Innovations include identifying changes to a kidney cell (cells of
renin lineage) following injury to another kidney cell (podocyte loss) in FSGS that recapitulate the aged
phenotype, and that these superimposed changes are very detrimental to the aged kidney.
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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Stuart James Shankland其他文献
Stuart James Shankland的其他文献
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{{ truncateString('Stuart James Shankland', 18)}}的其他基金
Targeting Podocyte-Endothelial Cell Crosstalk as a FSGS Therapy
靶向足细胞-内皮细胞串扰作为 FSGS 疗法
- 批准号:
10635547 - 财政年份:2023
- 资助金额:
$ 61.83万 - 项目类别:
Autocrine and paracrine podocyte signals decrease glomerular function/health in aged kidneys
自分泌和旁分泌足细胞信号会降低老年肾脏的肾小球功能/健康
- 批准号:
10698100 - 财政年份:2022
- 资助金额:
$ 61.83万 - 项目类别:
Kidney Aging Impairs Progenitor and Endocrine Function
肾脏老化损害祖细胞和内分泌功能
- 批准号:
10549835 - 财政年份:2020
- 资助金额:
$ 61.83万 - 项目类别:
Cell specific delivery of novel therapies to enhance glomerular regeneration and repair
细胞特异性递送新疗法以增强肾小球再生和修复
- 批准号:
10675681 - 财政年份:2020
- 资助金额:
$ 61.83万 - 项目类别:
Cell specific delivery of novel therapies to enhance glomerular regeneration and repair
细胞特异性递送新疗法以增强肾小球再生和修复
- 批准号:
10247521 - 财政年份:2020
- 资助金额:
$ 61.83万 - 项目类别:
Cell specific delivery of novel therapies to enhance glomerular regeneration and repair
细胞特异性递送新疗法以增强肾小球再生和修复
- 批准号:
10414816 - 财政年份:2020
- 资助金额:
$ 61.83万 - 项目类别:
Reduced Glomerular Progenitors Impair Regeneration in Aged Kidney
肾小球祖细胞减少会损害衰老肾脏的再生
- 批准号:
9329346 - 财政年份:2016
- 资助金额:
$ 61.83万 - 项目类别:
Rebuilding the glomerular filtration barrier by regenerating adult podocytes
通过再生成年足细胞重建肾小球滤过屏障
- 批准号:
9564892 - 财政年份:2015
- 资助金额:
$ 61.83万 - 项目类别:
Juxta-glomerular cells serve as glomerular epithelial cell progenitors in glomerular disease
肾小球旁细胞在肾小球疾病中充当肾小球上皮细胞祖细胞
- 批准号:
10436216 - 财政年份:2014
- 资助金额:
$ 61.83万 - 项目类别:
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