The Murine Dialysis Fistula Model Exhibits a Senescence Phenotype: Pathobiologic Mechanisms and Therapeutic Potential

小鼠透析瘘模型表现出衰老表型：病理生物学机制和治疗潜力

• 批准号: 10301011
• 负责人: KARL A. NATH
• 金额: $ 42.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-10 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301011
• 关键词: Accounting; Aging; Apoptosis; Apoptotic; Applications Grants; Arteries; Arteriovenous fistula; Automobile Driving; Biological Markers; Biology; Blood; Blood Vessels; Blood flow; CCL2 gene; CDKN2A gene; Cells; Characteristics; Chronic; Chronic Disease; Clinical; Clinical Trials; Cyclin-Dependent Kinase Inhibitor 2A; Data; Development; Dialysis procedure; Disease; End stage renal failure; Endothelium; Excision; Exhibits; Failure; Fistula; Functional disorder; Gelatinase A; Gelatinase B; Grant; Health Care Costs; Hemodialysis; Human; Impairment; Infection; Interleukin-6; Interruption; Intervention; Interventional radiology; Kidney Failure; Laboratories; Matrix Metalloproteinases; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Morbidity - disease rate; Mus; NF-kappa B; Operative Surgical Procedures; Outcome; Oxidative Stress; Participant; Pathologic; Pathway interactions; Patients; Phenotype; Plasminogen Activator Inhibitor 1; Predisposition; Process; Production; Publishing; Risk Factors; Rodent; Rodent Model; Role; Stains; Stress; Sum; Testing; Therapeutic; Thrombosis; Time; Up-Regulation; Uremia; Ursidae Family; Veins; age related; base; beta-Galactosidase; design; efficacy evaluation; frontier; hemodynamics; improved; in vivo; infection risk; inhibitor; interest; mortality; novel; novel therapeutic intervention; novel therapeutics; premature; prevent; response; senescence; shear stress; stressor; telomere; transcription factor

Vascular access dysfunction underlies much of the morbidity and mortality in ESRD and its healthcare costs. The arteriovenous fistula (AVF) is the favored access because of its lower risk for infection and thrombosis, and its greater functionality. AVF outcomes, however, are grim as 50% or more may never mature and function, and increasing numbers of once functional AVFs may, thereafter, cease to do so. Promoting AVF maturation and functionality is thus a dominant unmet need in CKD and ESRD. For more than 15 years, the PI's laboratory has investigated AVF rodent models and delineated vasculopathic and vasoprotective species in the AVF. For the past 2 years, this laboratory sought the basis for the range of maladaptive responses and observed that the AVF exhibits a senescence phenotype as assessed by multiple biomarkers and drivers of senescence. These findings, along with this lab's published data demonstrating marked upregulation of PAI-1, MCP-1, IL-6, MMPs, and other mediators, indicate that senescence is prematurely induced in the AVF. Using the murine AVF-CKD model introduced by this laboratory, three aims are proposed: Aim I: Define the role of specific stressors in initiating AVF senescence and impairing AVF outcomes. Hypothesis: The AVF imposes hemodynamic and other stress which veins were never designed to bear; such stress causes AVF senescence. Approach: This aim examines pathologic shear stress and the relative imbalance of vasculopathic (eg, NF-kB) over vasoprotective (eg, Klf2, Klf4, and Nrf2) transcription factors; oxidative stress; uremia; and age-related stress. Aim II: Define the roles of p16Ink4a and p21cip1 expressing cells in AVF senescence and impairing AVF outcomes. Hypothesis: p16Ink4a-expressing and p21cip1-expressing cells drive senescence, and deletion of senescent cells (SCs) improves the AVF. Approach: p16Ink4a-expressing cells will be deleted in the AVF using the INK-ATTAC mouse which enables the removal of p16-expressing SCs but not non-SCs; a conditional endothelial-specific INK-ATTAC mouse provides an added approach. The role of p21cip1-expressing SCs will be examined using p21+/+ and p21-/- mice and p21-ER-Cre mice which enable deletion of p21-expressing SCs. Aim III: Define the efficacy of senolytics, inhibitors of senescence-associated secretory phenotype (SASP), and inhibitors of specific SASP factors in improving AVF outcomes. Hypothesis: Interrupting senescence improves AVF maturation and function. Approach: SCs survive because of upregulated anti-apoptotic pathways. Inducing SC apoptosis (senolytics) provides a novel therapeutic approach, as do SASP-inhibitory agents. This aim examines the efficacy of senolytics, SASP inhibitors, and inhibitors of specific SASP factors (MCP-1 and IL-6) upregulated in human and rodent AVFs. In sum, this new R01 application examines a novel mechanism of AVF failure, namely, senescence; stressors that may cause it; mechanisms that may drive it; and therapeutic approaches that are part of the groundswell of interest in the therapeutic frontier of senolytics, the latter now entering clinical trials.

血管通路功能障碍是ESRD发病率和死亡率及其医疗费用的主要原因。 动静脉瘘（AVF）是首选的入路，因为其感染和血栓形成的风险较低， 以及它更强大的功能。然而，AVF的结果是严峻的，因为50%或更多可能永远不会成熟， 功能，并且增加数量的曾经起作用的AVF此后可能停止这样做。推广AVF 因此，成熟和功能性是CKD和ESRD中未满足的主要需求。15年多来， PI的实验室研究了AVF啮齿动物模型，并描述了血管病变和血管保护物种 在AVF。在过去的2年里，该实验室寻求适应不良反应范围的基础， 观察到AVF表现出衰老表型，如通过多种生物标志物和驱动因素评估的。 衰老这些发现，沿着本实验室发表的数据表明派-1的显著上调， MCP-1、IL-6、MMPs和其他介质表明AVF中过早诱导衰老。使用 本实验室引入的小鼠AVF-CKD模型，提出了三个目的：目的I：确定 特定应激源引发AVF衰老并损害AVF结局。假设：AVF 施加血液动力学和静脉从未设计承受的其他应力;此类应力导致AVF 衰老方法：本研究的目的是检查病理性切应力和 血管病变（如NF-κ B）超过血管保护（如Klf 2、Klf 4和Nrf 2）转录因子;氧化应激; 尿毒症;和年龄相关的压力。目的二：明确p16 Ink 4a和p21 cip 1表达细胞在AVF中的作用 衰老和损害AVF结果。假设：表达p16 Ink 4a和表达p21 cip 1的细胞 驱动衰老，并且衰老细胞（SC）的缺失改善AVF。方法：p16 Ink 4a表达 将使用INK-ATTAC小鼠在AVF中删除细胞，这使得能够去除表达p16的 SC而非非SC;条件性内皮特异性INK-ATTAC小鼠提供了一种额外的方法。的 将使用p21+/+和p21-/-小鼠以及p21-ER-Cre小鼠检测表达p21 cip 1的SC的作用， 能够删除表达p21的SC。目的III：定义衰老抑制剂的功效， 衰老相关的分泌表型（SASP），和特异性SASP因子的抑制剂， 改善AVF结局。假设：中断衰老改善AVF成熟和功能。 方法：由于上调的抗凋亡途径，SC存活。诱导SC凋亡（senolytics） 提供了一种新的治疗方法，如SASP抑制剂。这一目的是检验 衰老抑制剂、SASP抑制剂和在人中上调的特异性SASP因子（MCP-1和IL-6）的抑制剂 和啮齿动物动静脉瘘总之，这项新的R 01申请检查了AVF失效的新机制，即， 衰老;可能导致衰老的压力源;可能驱动衰老的机制;以及 这是对senolytics治疗前沿的兴趣高涨的一部分，后者现在正在进入临床试验。

项目成果

Does the Primacy of the Fistula Still Prevail in an Aging Hemodialysis Population?

在老龄化血液透析人群中，瘘管的首要地位是否仍然普遍存在？

• DOI: 10.1681/asn.0000000000000183
• 发表时间: 2023
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Nath,KarlA

GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle.

• DOI: 10.1172/jci.insight.171772
• 发表时间: 2023-11-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Marcotte, George R.;Miller, Matthew J.;Kunz, Hawley E.;Ryan, Zachary C.;Strub, Matthew D.;Vanderboom, Patrick M.;Heppelmann, Carrie J.;Chau, Sarah;Von Ruff, Zachary D.;Kilroe, Sean P.;Mckeen, Andrew T.;Dierdorff, Jason M.;Stern, Jennifer I.;Nath, Karl A.;Grueter, Chad E.;Lira, Vitor A.;Judge, Andrew R.;Rasmussen, Blake B.;Nair, K. Sreekumaran;Lanza, Ian R.;Ebert, Scott M.;Adams, Christopher M.
• 通讯作者: Adams, Christopher M.

Targeting lysine-specific demethylase 1A inhibits renal epithelial-mesenchymal transition and attenuates renal fibrosis.

靶向赖氨酸特异性脱甲基酶1a抑制肾上皮 - 间质转变并减弱肾纤维化。

• DOI: 10.1096/fj.202101566r
• 发表时间: 2022-01
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology