Role of KLF15 in proximal tubule metabolism

KLF15 在近曲小管代谢中的作用

基本信息

  • 批准号:
    10481366
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-01-01 至 2026-09-30
  • 项目状态:
    未结题

项目摘要

Chronic kidney disease (CKD) is a leading risk factor for cardiovascular disease, with a disproportionate burden on U.S. Veterans. Recent data demonstrates that acute kidney injury (AKI), despite initial renal recovery, is a major risk factor for CKD. The proximal tubule (PT) is the primary target in AKI due to its high susceptibility to ischemia and DNA-damaging nephrotoxins such as chemotherapeutic agents. Damaged PT cells dedifferentiate, and initially undergo cell cycle arrest, predominantly at the G2/M checkpoint. This cell cycle arrest may allow repair of DNA damage caused by reactive oxygen species secondary to mitochondrial damage or directly by DNA-damaging toxins. Sustained cell cycle arrest is associated with a switch to secretion of pro-fibrotic signaling molecules, inducing resident fibroblasts to proliferate and differentiate to myofibroblasts, beginning the transition to a fibrotic injury. PT cells also undergo metabolic reprograming, with severe downregulation of fatty acid b-oxidation (FAO), and limited compensation by anerobic glycolysis. While restoring FAO either by overexpressing Ppara or by using a peroxisome proliferator activated receptor alpha (PPARa) agonist attenuates AKI and CKD in murine models, this has not translated to use in clinical AKI, suggesting additional factors are required to mitigate the progression from AKI to CKD. Krüppel-Like Factor 15 (KLF15) is a kidney-enriched transcription factor, involved in a diverse range of cellular processes, including cell differentiation and FAO. In the initial funding period of the VA Merit, we demonstrated the salutary role of KLF15 in glomerular disease leading to a composition-of-matter IP on KLF15 agonists by the Veterans Affairs. During this initial period, we also identified that KLF15 is highly expressed in differentiated PT cells, but is significantly reduced in murine models of PT injury. Utilizing a murine model of PT-specific injury secondary to DNA damage, we observed that PT-specific knockdown of Klf15 exacerbated AKI as well as CKD. PT-specific knockdown of Klf15 also increased pathways involving cell cycle arrest, oxidative stress, pro-fibrotic signaling and a decrease in pathways utilizing FA for the generation of acetyl-CoA, a central metabolic intermediate in macromolecule biosynthesis and energy production. We also observed an enrichment of genes critical for FA utilization with putative and proximal KLF15- and PPARa-binding sites, suggesting potential KLF15-PPARa co-operativity in the regulation of FA utilization. In addition, we demonstrated a significant increase in glycerolipid synthesis pathways and lipid droplet formation in the setting of suppressed FAO, suggesting a potential compensatory mechanism post-DNA damage. KLF15 expression was also associated with PPARA expression in human kidney biopsies with and without CKD. In addition, multivariate regression analysis demonstrated that a decrease in KLF15 expression was independently associated with eGFR decline, suggesting that the loss of KLF15 might be a key driver of PT injury. Based on these preliminary data and strong scientific rigor of prior research, we hypothesize that KLF15-PPARa co-operativity drives the utilization of excess free fatty acids for acetyl-CoA and glycerolipid synthesis to prevent maladaptive PT repair post-DNA damage. We propose to test this hypothesis by (1) determining the mechanism by which KLF15-PPARa co-operativity restores PT metabolism after PT injury secondary to DNA-damage and (2) to investigate the requisite role of KLF15-PPARa in PT injury secondary to DNA-damage. This proposal will address a current gap in the field by investigating the mechanisms mediating transcriptional regulation of FA utilization in the PT cells post-DNA damage. The long-term goal of our project is to demonstrate that the combination of KLF15 and PPARa agonists is a novel therapeutic strategy to mitigate PT injury post-DNA damage. Identification of novel targets for the treatment of AKI is of major interest to the VA, given the high burden of CKD among U.S. Veterans.
慢性肾脏疾病(CKD)是心血管疾病的主要危险因素

项目成果

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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:
    --
  • 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:
    --
  • 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:
    --
  • 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:
    --
  • 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:
    --
  • 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:
    --
  • 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:
    9918361
  • 财政年份:
    2017
  • 资助金额:
    --
  • 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:
    --
  • 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:
    --
  • 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:
    --
  • 项目类别:
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