Application of Progenitor Niche Signals to Ex Vivo Nephrogenesis
祖细胞生态位信号在离体肾发生中的应用
基本信息
- 批准号:10260117
- 负责人:
- 金额:$ 53.03万
- 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:2020-09-15 至 2022-09-14
- 项目状态:已结题
- 来源:
- 关键词:AddressAmericanAnatomyAnimalsAssesBiological AssayBiological MarkersBlood VesselsCellsChronic Kidney FailureClinicalCommunitiesComplexDialysis patientsDialysis procedureEmbryoEnd stage renal failureEngineeringEngraftmentEpithelialEpitheliumGenerationsGoalsHumanImageImplantIn VitroIndividualInjuryInjury to KidneyKidneyKidney DiseasesKidney TransplantationLifeMaintenanceMechanicsModificationMusNephronsOrganOrganogenesisOrganoidsPathway interactionsPatientsPatternPharmacologyPhysiologicalProtocols documentationRegenerative responseRenal Replacement TherapyRenal TissueRenal functionResearchResourcesRoleSignal PathwaySignal TransductionSiteSourceStructureSurvival RateTechniquesTechnologyTestingTimeTissue GraftsTissuesTransplantationTubular formationUrinary systemVascular Graftcell typeimprovedin vivointravital microscopynephrogenesisnovelnovel therapeuticspreventprogenitortechnology developmenttoolurinary
项目摘要
Summary
Approximately 750,000 Americans have end stage renal disease, in which kidney
function is insufficient to sustain life. Organ function can be supplemented by dialysis in these
individuals, however the 10 year survival rate for individuals on dialysis is just over 10%.
Survival rates are much better for patients receiving a kidney transplant, but organ supply does
not match demand. Ex vivo organogenesis has the potential to provide functional tissue for
renal replacement therapy. Furthermore, defining signals that functionally direct nephrogenesis
may identify pathways that can be manipulated to augment the regenerative response of the
injured kidney in vivo. Several groups, including our own, have established techniques that
allow us to generate cellularly complex kidney organoids derived from human and mouse
induced pluripotent cells. These tissues seem an ideal source for generating renal replacement
tissue. Theoretically, one would take patient-derived renal organoids and transplant them onto a
diseased kidney, where they would integrate with the host urinary system and improve renal
function. Although several groups have attempted to perform these types of transplantations,
there is no evidence to date that they functionally integrate with the host kidney. In our
preliminary studies, we have identified three key obstacles that must be overcome in order to
generate ex vivo renal organoids that integrate with the host. First, organoid structure is
relatively disorganized, which is in contrast to the precise arrangement of cell types along the
cortical-medullary axis of healthy, native kidneys. Second, with current strategies, organoid-
derived tubules do not connect with host-derived tubules and the organoid-derived tubules
involute over time. Third, we lack robust functional assays to identify experimental modifications
that improve organoid function. Each of these barriers must be eliminated to generate functional
organoids that can be clinically beneficial to patients.
We hypothesize that the best approach to achieve integrated organoid tissue is to
selectively generate cell types that match the anatomic site of engraftment. Specifically, we will
identify conditions that will allow us to generate proximal nephrons, including glomeruli and
proximal tubules with their associated interstitium and vasculature, (herein referred to as cortical
organoids) for the purposes of engraftment. To this end, our strategy for ex vivo nephron
generation is unique in its emphasis on promoting the anatomically “correct” epithelia and its
microenvironment for the site of engraftment. Concurrent to this, we will identify factors and
techniques that promote tubule-tubule fusion. Thus, once we have generated cortical organoids,
we will utilize this technology to stimulate the tubules of the graft to anastomose with the tubules
of the host. Finally, we will use live imaging and well-defined functional assays as a readout of
tubular function to continually optimize our strategy. The long-term goal of this proposal is to
engineer organized, ex vivo renal tissue that can be induced to form functional nephrons
in animal hosts through novel grafting strategies.
Summary
Approximately 750,000 Americans have end stage renal disease, in which kidney
function is insufficient to sustain life. Organ function can be supplemented by dialysis in these
individuals, however the 10 year survival rate for individuals on dialysis is just over 10%.
Survival rates are much better for patients receiving a kidney transplant, but organ supply does
not match demand. Ex vivo organogenesis has the potential to provide functional tissue for
renal replacement therapy. Furthermore, defining signals that functionally direct nephrogenesis
may identify pathways that can be manipulated to augment the regenerative response of the
injured kidney in vivo. Several groups, including our own, have established techniques that
allow us to generate cellularly complex kidney organoids derived from human and mouse
induced pluripotent cells. These tissues seem an ideal source for generating renal replacement
tissue. Theoretically, one would take patient-derived renal organoids and transplant them onto a
diseased kidney, where they would integrate with the host urinary system and improve renal
function. Although several groups have attempted to perform these types of transplantations,
there is no evidence to date that they functionally integrate with the host kidney. In our
preliminary studies, we have identified three key obstacles that must be overcome in order to
generate ex vivo renal organoids that integrate with the host. First, organoid structure is
relatively disorganized, which is in contrast to the precise arrangement of cell types along the
cortical-medullary axis of healthy, native kidneys. Second, with current strategies, organoid-
derived tubules do not connect with host-derived tubules and the organoid-derived tubules
involute over time. Third, we lack robust functional assays to identify experimental modifications
that improve organoid function. Each of these barriers must be eliminated to generate functional
organoids that can be clinically beneficial to patients.
We hypothesize that the best approach to achieve integrated organoid tissue is to
selectively generate cell types that match the anatomic site of engraftment. Specifically, we will
identify conditions that will allow us to generate proximal nephrons, including glomeruli and
proximal tubules with their associated interstitium and vasculature, (herein referred to as cortical
organoids) for the purposes of engraftment. To this end, our strategy for ex vivo nephron
generation is unique in its emphasis on promoting the anatomically “correct” epithelia and its
microenvironment for the site of engraftment. Concurrent to this, we will identify factors and
techniques that promote tubule-tubule fusion. Thus, once we have generated cortical organoids,
we will utilize this technology to stimulate the tubules of the graft to anastomose with the tubules
of the host. Finally, we will use live imaging and well-defined functional assays as a readout of
tubular function to continually optimize our strategy. The long-term goal of this proposal is to
engineer organized, ex vivo renal tissue that can be induced to form functional nephrons
in animal hosts through novel grafting strategies.
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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Thomas Joseph Carroll其他文献
NuMI Beam Monitoring Simulation and Data Analysis
NuMI 光束监测仿真和数据分析
- DOI:
10.3390/psf2023008073 - 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Yiding Yu;Thomas Joseph Carroll;Sudeshna Ganguly;Karol Lang;Eduardo Ossorio;P. Snopok;Jennifer Thomas;D. A. Wickremasinghe;K. Yonehara - 通讯作者:
K. Yonehara
Thomas Joseph Carroll的其他文献
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{{ truncateString('Thomas Joseph Carroll', 18)}}的其他基金
Application of Progenitor Niche Signals to Ex Vivo Nephrogenesis
祖细胞生态位信号在离体肾发生中的应用
- 批准号:
10670749 - 财政年份:2021
- 资助金额:
$ 53.03万 - 项目类别:
The Role of Renal Interstitium in Kidney Development
肾间质在肾脏发育中的作用
- 批准号:
10316848 - 财政年份:2021
- 资助金额:
$ 53.03万 - 项目类别:
Application of Progenitor Niche Signals to Ex Vivo Nephrogenesis
祖细胞生态位信号在离体肾发生中的应用
- 批准号:
10295980 - 财政年份:2021
- 资助金额:
$ 53.03万 - 项目类别:
The Role of Renal Interstitium in Kidney Development
肾间质在肾脏发育中的作用
- 批准号:
10445327 - 财政年份:2021
- 资助金额:
$ 53.03万 - 项目类别:
The Role of Renal Interstitium in Kidney Development
肾间质在肾脏发育中的作用
- 批准号:
10621859 - 财政年份:2021
- 资助金额:
$ 53.03万 - 项目类别:
Application of progenitor niche signals to ex vivo nephrogenesis
祖细胞生态位信号在离体肾发生中的应用
- 批准号:
9981392 - 财政年份:2019
- 资助金额:
$ 53.03万 - 项目类别:
Application of progenitor niche signals to ex vivo nephrogenesis
祖细胞生态位信号在离体肾发生中的应用
- 批准号:
9297088 - 财政年份:2015
- 资助金额:
$ 53.03万 - 项目类别:
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