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。 动静脉内瘘 (AVF) 是首选的入路，因为其感染和血栓形成的风险较低， 及其更强大的功能。然而，AVF 的结果很严峻，因为 50% 或更多的患者可能永远不会成熟，并且 功能，并且越来越多的曾经起作用的 AVF 此后可能会停止这样做。推广 AVF 因此，成熟度和功能性是 CKD 和 ESRD 中未满足的主要需求。超过 15 年以来， PI 实验室研究了 AVF 啮齿动物模型并确定了血管病变和血管保护物种 在 AVF 中。在过去的两年里，该实验室寻找适应不良反应范围的基础， 观察到 AVF 表现出衰老表型，通过多种生物标志物和驱动因素评估 衰老。这些发现以及该实验室发表的数据表明 PAI-1 显着上调， MCP-1、IL-6、MMP 和其他介质表明 AVF 过早诱导衰老。使用 本实验室推出的小鼠 AVF-CKD 模型，提出了三个目标： 目标 I：定义角色 启动 AVF 衰老和损害 AVF 结果的特定压力源。假设：AVF 施加静脉无法承受的血流动力学和其他压力；这种压力会导致 AVF 衰老。方法：该目的检查病理剪应力和相对不平衡 血管病变（例如 NF-kB）转录因子优于血管保护（例如 Klf2、Klf4 和 Nrf2）转录因子；氧化应激； 尿毒症；以及与年龄有关的压力。目标 II：定义 p16Ink4a 和 p21cip1 表达细胞在 AVF 中的作用 衰老并损害 AVF 结局。假设：表达 p16Ink4a 和表达 p21cip1 的细胞 驱动衰老，删除衰老细胞 (SC) 可改善 AVF。方法：p16Ink4a-表达 使用 INK-ATTAC 小鼠删除 AVF 中的细胞，从而去除表达 p16 的细胞 SC 但非 SC 除外；条件性内皮特异性 INK-ATTAC 小鼠提供了一种额外的方法。这 将使用 p21+/+ 和 p21-/- 小鼠以及 p21-ER-Cre 小鼠检查表达 p21cip1 的 SC 的作用， 能够删除表达 p21 的 SC。目标 III：定义 senolytics、抑制剂的功效 衰老相关分泌表型 (SASP) 以及特定 SASP 因子的抑制剂 改善 AVF 的结果。假设：中断衰老可以改善 AVF 的成熟和功能。 方法：SC 之所以能够存活，是因为抗凋亡途径上调。诱导 SC 凋亡（senolytics） 与 SASP 抑制剂一样，它提供了一种新的治疗方法。该目的旨在检验以下方法的功效： senolytics、SASP 抑制剂和特定 SASP 因子（MCP-1 和 IL-6）的抑制剂在人体中上调 和啮齿动物 AVF。总之，这个新的 R01 应用研究了 AVF 失败的一种新机制，即 衰老;可能导致这种情况的压力源；可能驱动它的机制；以及治疗方法 这是人们对 senolytics 治疗前沿兴趣高涨的一部分，后者现已进入临床试验。

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

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

• 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

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.