Transcriptional control of mitochondrial function by KLF6 in diabetic kidney disease
KLF6 在糖尿病肾病中对线粒体功能的转录控制
基本信息
- 批准号:9918361
- 负责人:
- 金额:$ 34.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-06-12 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:Activities of Daily LivingAddressAdultAlbuminuriaAmericanApoptosisAttenuatedBindingBiogenesisCatalytic DomainCellular StressCenters for Disease Control and Prevention (U.S.)Chronic Kidney FailureComplexDNA DamageDataDiabetes MellitusDiabetic NephropathyDisease ProgressionEmbryoEnd stage renal failureEndotheliumEpithelial CellsExhibitsFiltrationGene ChipsGene ExpressionGenesGenetic TranscriptionGlucoseGoalsHumanIndividualInjuryInsulin-Dependent Diabetes MellitusKidneyKineticsKnock-in MouseKnockout MiceLaboratoriesLightMediatingMitochondriaMitochondrial DNAMitochondrial DiseasesMusMutationNPHS2 proteinNon-Insulin-Dependent Diabetes MellitusOutcomes ResearchPPAR gammaPathway interactionsPhysiologic pulsePost-Translational Protein ProcessingProteinuriaProteomicsReportingResearchResearch ProposalsRisk FactorsRoleSeveritiesStreptozocinStructureSystemTamoxifenTetanus Helper PeptideTranscriptTranscriptional RegulationUnited StatesWild Type MouseZinc Fingersbasecomplex IVcytochrome ccytochrome c oxidasediabeticdruggable targetglomerular filtrationglycemic controlimprovedinducible gene expressionkidney biopsyknock-downmitochondrial dysfunctionmouse modelnoveloverexpressionpodocytepreventpromoterprotein expressionrespiratoryresponse to injurytranscription factor
项目摘要
Project Summary/Abstract
The Centers for Disease Control and Prevention estimates more than 10% of adults in the United States, over
20 million Americans have chronic kidney disease. Diabetes Mellitus is the leading risk factor for chronic
kidney disease in the United States. Despite improved glycemic control, individuals with Diabetes Mellitus
continue to develop and progress to diabetic kidney disease (DKD). In DKD, along with endothelial injury and
mesangial expansion, podocyte loss directly contributes to the functional capacity to maintain the renal filtration
barrier. Mitochondrial injury is also uniformly observed in DKD and is accompanied by mitochondrial DNA
damage as well as altered expression of genes involved in mitochondrial biogenesis, function, and
fragmentation. We recently reported the essential role for the zinc-finger transcription factor, Krüppel-like factor
6 (KLF6), in podocyte injury. Specifically, we demonstrated that KLF6 is an early inducible injury response
gene that enhances mitochondrial respiratory complex IV (cytochrome c oxidase, COX) expression, thereby
abrogating the release of cytochrome c and activation of apoptosis in the setting of cell stress. KLF6 maintains
COX assembly by regulating the expression of key transcripts involved in mitochondrial replication,
transcription, and function under cell stress. To date, this is the first study demonstrating a direct regulatory
effect of a zinc-finger transcription factor on mitochondrial function in the podocyte. Our preliminary data also
suggests that podocyte-specific loss of Klf6 (Klf6-/-) accelerated DKD in mice. In addition, we observed a
significant increase in mitochondrial injury with podocyte loss in the diabetic Klf6-/- mice as compared to
diabetic wildtype mice. Furthermore, we observed that modulating the level of KLF6 expression in the podocyte
directly regulated mitochondrial structure, function, genes involved in COX assembly, and apoptosis. Finally,
KLF6 expression was reduced in DKD as compared to healthy control subjects in three independent gene
expression arrays from human kidney biopsies. The objective of this research proposal is to demonstrate
that KLF6 is required to prevent mitochondrial dysfunction and podocyte injury in DKD. The long-term goal of
our project is to identify “druggable” targets in restoring mitochondrial function in podocytes of diabetic kidney.
This proposal will address a current gap in the field by demonstrating that COX assembly is critical to
preventing mitochondrial dysfunction in podocytes of diabetic kidney. The potential impact of this proposed
research is that it will shed new light on the critical role of respiratory complex assembly in improving
mitochondrial function in the podocyte and slowing the rate of DKD progression in the kidney. Finally,
deciphering the mechanism by which KLF6 regulates COX assembly will provide us with a novel pathway to
target in DKD.
项目总结/文摘
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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Sandeep K Mallipattu其他文献
The Prevalence of Post-Acute Sequelae of COVID-19 in Solid Organ Transplant Recipients: Evaluation of Risk in the National COVID Cohort Collaborative (N3C).
实体器官移植受者中 COVID-19 急性后遗症的患病率:国家 COVID 队列协作组织 (N3C) 的风险评估。
- DOI:
10.1016/j.ajt.2024.06.001 - 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
A. Vinson;Makayla Schissel;A. Anzalone;Ran Dai;E. French;A. Olex;Stephen B. Lee;Michael Ison;R. Mannon;A. Wilcox;Adam M. Lee;Alexis Graves;A. Anzalone;A. Manna;Amit Saha;A. Olex;Andrea Zhou;Andrew E. Williams;Andrew Southerland;A. Girvin;Anita Walden;Anjali A. Sharathkumar;B. Amor;Benjamin Bates;Brian Hendricks;Brijesh Patel;Caleb Alexander;Carolyn T Bramante;C. Ward‐Caviness;C. Madlock;Christine Suver;C. Chute;Christopher Dillon;Chunlei Wu;Clare Schmitt;Cliff Takemoto;D. Housman;D. Gabriel;David A. Eichmann;Diego Mazzotti;Don Brown;Eilis Boudreau;Elaine Hill;Elizabeth Zampino;E. Marti;Emily Pfaff;E. French;F. Koraishy;Federico Mariona;Fred Prior;G. Sokos;Greg Martin;H. Lehmann;Heidi Spratt;Hemalkumar Mehta;Hongfang Liu;Hythem Sidky;J. Hayanga;Jami D. Pincavitch;Jaylyn F. Clark;Jeremy Harper;Jessica Islam;Jin Ge;J. Gagnier;J. Saltz;J. Saltz;Johanna J. Loomba;Jon D. Buse;Jomol P Mathew;J. Rutter;J. McMurry;Justin Guinney;J. Starren;Kay Crowley;K. Bradwell;Kellie M. Walters;K. Wilkins;Kenneth R. Gersing;K. Cato;Kimberly Murray;K. Kostka;Lavance Northington;Lee A. Pyles;Leonie Misquitta;Lesley Cottrell;L. Portilla;Mariam Deacy;Mark Bissell;M. Clark;M. Emmett;M. Saltz;M. Palchuk;Melissa A. Haendel;Meredith Adams;Meredith Temple;Michael G. Kurilla;Michele Morris;N. Qureshi;Nasia Safdar;Nicole Garbarini;Noha Sharafeldin;O. Sadan;P. A. Francis;P. W. Burgoon;Peter Robinson;Philip R. O. Payne;Rafael Fuentes;R. Jawa;Rebecca Erwin;Rena C Patel;Richard A. Moffitt;R. Zhu;R. Kamaleswaran;R. Hurley;Robert T. Miller;S. Pyarajan;Sam G. Michael;Samuel Bozzette;Sandeep K Mallipattu;Satyanarayana Vedula;Scott A. Chapman;Shawn T O'Neil;Soko Setoguchi;Stephanie S. Hong;Steve Johnson;Tellen D. Bennett;Tiffany J. Callahan;Umit Topaloglu;Usman Sheikh;Valery Gordon;V. Subbian;Warren Kibbe;Wenndy Hernandez;Willarene P. Beasley;W. Cooper;W. Hillegass;X. Zhang - 通讯作者:
X. Zhang
Sandeep K Mallipattu的其他文献
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{{ truncateString('Sandeep K Mallipattu', 18)}}的其他基金
Single-cell Cyclic Multiplex in Situ Tagging to Advance Kidney Research
单细胞循环多重原位标记促进肾脏研究
- 批准号:
10790122 - 财政年份:2023
- 资助金额:
$ 34.9万 - 项目类别:
Small Molecule KLF15 Agonists for Kidney Disease
治疗肾脏疾病的小分子 KLF15 激动剂
- 批准号:
10553107 - 财政年份:2021
- 资助金额:
$ 34.9万 - 项目类别:
Small Molecule KLF15 Agonists for Kidney Disease
治疗肾脏疾病的小分子 KLF15 激动剂
- 批准号:
10117332 - 财政年份:2021
- 资助金额:
$ 34.9万 - 项目类别:
Small Molecule KLF15 Agonists for Kidney Disease
治疗肾脏疾病的小分子 KLF15 激动剂
- 批准号:
10359057 - 财政年份:2021
- 资助金额:
$ 34.9万 - 项目类别:
ShEEP Request for High-throughput Single Cell Genomics Instrumentation
ShEEP 请求高通量单细胞基因组学仪器
- 批准号:
9795153 - 财政年份:2019
- 资助金额:
$ 34.9万 - 项目类别:
Role of KLF15 in proximal tubule metabolism
KLF15 在近曲小管代谢中的作用
- 批准号:
10481366 - 财政年份:2018
- 资助金额:
$ 34.9万 - 项目类别:
Transcriptional control of mitochondrial function by KLF6 in diabetic kidney disease
KLF6 在糖尿病肾病中对线粒体功能的转录控制
- 批准号:
10400042 - 财政年份:2017
- 资助金额:
$ 34.9万 - 项目类别:
Transcriptional control of mitochondrial function by KLF6 in diabetic kidney disease
KLF6 在糖尿病肾病中对线粒体功能的转录控制
- 批准号:
9286505 - 财政年份:2017
- 资助金额:
$ 34.9万 - 项目类别:
The Role of KLF15 as a transcriptional regulator of podocyte differentiation
KLF15 作为足细胞分化转录调节因子的作用
- 批准号:
8750137 - 财政年份:2014
- 资助金额:
$ 34.9万 - 项目类别:
The Role of KLF15 as a transcriptional regulator of podocyte differentiation
KLF15 作为足细胞分化转录调节因子的作用
- 批准号:
8916713 - 财政年份:2014
- 资助金额:
$ 34.9万 - 项目类别:
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