Safety and Efficacy of Human Clinical Trials Using Kidney-on-a-Chip Microphysiological Systems
使用芯片肾微生理系统进行人体临床试验的安全性和有效性
基本信息
- 批准号:10471014
- 负责人:
- 金额:$ 7.56万
- 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:2020-07-15 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAffectAnimal ModelArchitectureAutosomal Dominant Polycystic KidneyBioinformaticsBiological ModelsBiologyBiomedical EngineeringBiomedical ResearchBiometryBlood VesselsCause of DeathCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeClinicalClinical TrialsClinical Trials DesignClustered Regularly Interspaced Short Palindromic RepeatsComplexComputational BiologyDataDevelopmentDevicesDiseaseDisease modelEngineeringEtiologyExpenditureFailureFocal Segmental GlomerulosclerosisFundingGene Expression ProfilingGenesGeneticGenomicsGoalsHeterogeneityHistologicHistopathologyHumanHuman GeneticsImageIn VitroIndividualInternal MedicineKidneyKidney DiseasesKidney FailureMedicareMicrofluidicsModelingModernizationMolecularMolecular ProfilingMolecular and Cellular BiologyNatural HistoryNephrologyNephronsNephrotic SyndromeOrganoidsOutcomePathogenesisPathologyPathway interactionsPatientsPharmacology and ToxicologyPhenotypePhysiologicalPhysiological ProcessesPhysiologyPluripotent Stem CellsPolycystic Kidney DiseasesPublic HealthPublishingRandomized Clinical TrialsRare DiseasesReportingResourcesSafetyStructureSystemTaxonomyTechnologyTestingTherapeuticTissue MicroarrayTranslatingTriad Acrylic ResinTubular formationUnited States National Institutes of Healthbasebiomarker discoverybiomarker evaluationclinical phenotypeclinically relevantcohortdesigndifferentiation protocoldrug developmenteffective therapyglomerular filtrationin vitro Modelin vivoinsightkidney cellkidney vascular structurematerials sciencemedical specialtiesmicrophysiology systemmodel developmentmultidisciplinarynovelnovel therapeuticsorgan on a chipoutcome predictionpatient responsepatient stratificationphenotypic dataprecision medicineprofiles in patientsprotocol developmentresponseresponse to injurystem cell biologysuccesstargeted therapy trialstherapeutic evaluationtool
项目摘要
ABSTRACT
Kidney diseases are an expanding public health problem, currently affecting 37 million people and are the 9th
leading cause of death in the US, while disproportionately accounting for ~27% of Medicare expenditures.
Unfortunately, the number of randomized clinical trials has been fewer than all other specialties of internal
medicine with very low success rates, likely due to the structural and functional complexity of the kidney. The
multicellular architecture and unusual triad of physiological processes characterized by glomerular filtration,
tubular secretion, and tubular reabsorption have limited the ability of animal models to recapitulate the diversity
of etiologies, mechanisms, and heterogenous manifestations of most human kidney diseases. Additionally,
until recently there has been a lack of in vitro models that recapitulate critical aspects of kidney physiology,
mimic the unique complexities of specific nephron segments, or assess reparative mechanisms in response
to injury. In response to this critical unmet need, our group has pioneered the development of `human kidney
on a chip' microphysiological systems (MPS). Our integrated approach for in vitro disease modeling includes
differentiating human kidney cells and organoids from diseased patient-derived inducible pluripotent stem cells
(iPSCs), CRISPR gene editing, single cell transcriptional profiling and engineered MPS platforms for both
living human kidney vascular networks and tubular units. This approach has already led us to achieve new
mechanistic insights into the pathogenesis of autosomal dominant polycystic kidney disease (PKD, the leading
monogenetic cause of kidney failure) and potential new therapeutic pathways. In parallel, significant efforts
led by us are underway in the Nephrotic Syndrome Study Network (known as NEPTUNE) and the Kidney
Precision Medicine Project, NIH funded Consortia designed to address the functional heterogeneity of kidney
disease by rigorous molecular, histologic and phenotypic characterization of kidney diseases. The NCATS
Rare Disease Clinical Network NEPTUNE is testing the precision medicine concept by matching individual
molecular profiles from patients to targeted therapy trials. We now propose to leverage these field-leading
tools to inform clinical trial design and planning, accounting for human genetic and clinical response
heterogeneity for PKD and Focal Segmental Glomerulosclerosis (FSGS), the form of nephrotic syndrome with
the most severe patient consequences. Based on our data, we hypothesize that kidney-on-a-chip MPS will
manifest patient-specific phenotypic responses in vitro commensurate with clinical trial outcomes in vivo,
establishing a robust molecular and cellular basis for kidney precision medicine approaches. We have
established a multidisciplinary investigative team with all the field-leading expertise needed to address all
technical and experimental challenges.
摘要
肾脏疾病是一个不断扩大的公共卫生问题,目前影响着3700万人,
这是美国死亡的主要原因,同时不成比例地占医疗保险支出的27%。
不幸的是,随机临床试验的数量一直少于所有其他专业的内部
这种药物的成功率非常低,可能是由于肾脏的结构和功能复杂性。的
多细胞结构和以肾小球滤过为特征的不寻常的三重生理过程,
肾小管分泌和肾小管重吸收限制了动物模型重现多样性的能力,
病因学,机制和大多数人类肾脏疾病的异质性表现。此外,本发明还
直到最近还缺乏概括肾生理学关键方面的体外模型,
模拟特定肾单位节段的独特复杂性,或评估反应中的修复机制,
受伤。为了满足这一关键的未满足的需求,我们的团队率先开发了“人类肾脏”。
芯片上的微生理系统(MPS)。我们用于体外疾病建模的综合方法包括
从患病患者来源的诱导性多能干细胞分化人肾细胞和类器官
(iPSCs)、CRISPR基因编辑、单细胞转录谱分析和工程化MPS平台,
活的人类肾脏血管网络和管状单位。这种方法已经使我们实现了新的
常染色体显性遗传性多囊肾病(PKD)的发病机制的见解,
肾衰竭的单基因原因)和潜在的新治疗途径。与此同时,
由我们领导的肾病综合征研究网络(称为NEPTUNE)和肾脏
NIH资助的精准医学项目财团旨在解决肾脏功能异质性问题
通过严格的分子、组织学和表型表征,对肾脏疾病进行研究。NCATS
罕见病临床网络NEPTUNE正在通过匹配个人来测试精准医疗概念
从患者到靶向治疗试验的分子图谱。我们现在建议利用这些领域领先的
为临床试验设计和规划提供信息的工具,说明人类遗传和临床反应
PKD和局灶节段性肾小球硬化症(FSGS)的异质性,
最严重的患者后果。根据我们的数据,我们假设肾芯片MPS将
在体外表现出与体内临床试验结果相当的患者特异性表型应答,
为肾脏精准医学方法建立了强大的分子和细胞基础。我们有
建立了一个多学科调查小组,拥有处理所有
技术和实验挑战。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Modelling ciliopathy phenotypes in human tissues derived from pluripotent stem cells with genetically ablated cilia.
在具有遗传烧蚀的纤毛的多能干细胞中衍生出的人体组织中的纤毛病表型。
- DOI:10.1038/s41551-022-00880-8
- 发表时间:2022-04
- 期刊:
- 影响因子:28.1
- 作者:
- 通讯作者:
Engraftment of Kidney Organoids In Vivo.
- DOI:10.1007/s40472-023-00397-2
- 发表时间:2023
- 期刊:
- 影响因子:2.1
- 作者:Freedman, Benjamin S;Dekel, Benjamin
- 通讯作者:Dekel, Benjamin
Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice.
- DOI:10.1126/scitranslmed.abn1252
- 发表时间:2022-05-25
- 期刊:
- 影响因子:17.1
- 作者:Hunt, Andrew C.;Case, James Brett;Park, Young-Jun;Cao, Longxing;Wu, Kejia;Walls, Alexandra C.;Liu, Zhuoming;Bowen, John E.;Yeh, Hsien-Wei;Saini, Shally;Helms, Louisa;Zhao, Yan Ting;Hsiang, Tien-Ying;Starr, Tyler N.;Goreshnik, Inna;Kozodoy, Lisa;Carter, Lauren;Ravichandran, Rashmi;Green, Lydia B.;Matochko, Wadim L.;Thomson, Christy A.;Vogeli, Bastian;Kruger, Antje;VanBlargan, Laura A.;Chen, Rita E.;Ying, Baoling;Bailey, Adam L.;Kafai, Natasha M.;Boyken, Scott E.;Ljubetic, Ajasja;Edman, Natasha;Ueda, George;Chow, Cameron M.;Johnson, Max;Addetia, Amin;Navarro, Mary-Jane;Panpradist, Nuttada;Gale, Michael, Jr.;Freedman, Benjamin S.;Bloom, Jesse D.;Ruohola-Baker, Hannele;Whelan, Sean P. J.;Stewart, Lance;Diamond, Michael S.;Veesler, David;Jewett, Michael C.;Baker, David
- 通讯作者:Baker, David
Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease.
- DOI:10.1038/s41467-022-35537-2
- 发表时间:2022-12-23
- 期刊:
- 影响因子:16.6
- 作者:Li, Sienna R.;Gulieva, Ramila E.;Helms, Louisa;Cruz, Nelly M.;Vincent, Thomas;Fu, Hongxia;Himmelfarb, Jonathan;Freedman, Benjamin S.
- 通讯作者:Freedman, Benjamin S.
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jonathan Himmelfarb其他文献
Jonathan Himmelfarb的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jonathan Himmelfarb', 18)}}的其他基金
KPMP Kidney Mapping and Atlas Project (KMAP)
KPMP 肾脏绘图和图集项目 (KMAP)
- 批准号:
10492787 - 财政年份:2022
- 资助金额:
$ 7.56万 - 项目类别:
KPMP Kidney Mapping and Atlas Project (KMAP)
KPMP 肾脏绘图和图谱项目 (KMAP)
- 批准号:
10705740 - 财政年份:2022
- 资助金额:
$ 7.56万 - 项目类别:
Safety and Efficacy of Human Clinical Trials Using Kidney-on-a-Chip Microphysiological Systems
使用芯片肾微生理系统进行人体临床试验的安全性和有效性
- 批准号:
10037553 - 财政年份:2020
- 资助金额:
$ 7.56万 - 项目类别:
Safety and Efficacy of Human Clinical Trials Using Kidney-on-a-Chip Microphysiological Systems
使用芯片肾微生理系统进行人体临床试验的安全性和有效性
- 批准号:
10671573 - 财政年份:2020
- 资助金额:
$ 7.56万 - 项目类别:
Safety and Efficacy of Human Clinical Trials Using Kidney-on-a-Chip Microphysiological Systems
使用芯片肾微生理系统进行人体临床试验的安全性和有效性
- 批准号:
10216377 - 财政年份:2020
- 资助金额:
$ 7.56万 - 项目类别:
Safety and Efficacy of Human Clinical Trials Using Kidney-on-a-Chip Microphysiological Systems
使用芯片肾微生理系统进行人体临床试验的安全性和有效性
- 批准号:
10515788 - 财政年份:2020
- 资助金额:
$ 7.56万 - 项目类别:
Effects of microgravity on the structure and function of proximal and distal tubule MPS
微重力对近远曲小管MPS结构和功能的影响
- 批准号:
9890028 - 财政年份:2017
- 资助金额:
$ 7.56万 - 项目类别:
A Microphysiological System for Kidney Disease Modeling and Drug Efficacy Testing
用于肾脏疾病建模和药效测试的微生理系统
- 批准号:
9757837 - 财政年份:2017
- 资助金额:
$ 7.56万 - 项目类别:
A Microphysiological System for Kidney Disease Modeling and Drug Efficacy Testing
用于肾脏疾病建模和药效测试的微生理系统
- 批准号:
9975953 - 财政年份:2017
- 资助金额:
$ 7.56万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 7.56万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 7.56万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 7.56万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 7.56万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 7.56万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 7.56万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 7.56万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 7.56万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 7.56万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 7.56万 - 项目类别:
Research Grant