Regulation of Lymphatic and Vascular Remodeling in Acute Kidney Injury

急性肾损伤中淋巴和血管重塑的调节

• 批准号: 10750349
• 负责人: Gelare Ghajar-Rahimi
• 金额: $ 4.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750349
• 关键词: 3-Dimensional; Acute Renal Failure with Renal Papillary Necrosis; Affect; Architecture; Area; Bilateral; Binding; Bioinformatics; Blood; Blood Vessels; Blood capillaries; Cells; Chronic Kidney Failure; Cisplatin; Clinical; Clinical Trials; Coculture Techniques; Cohort Studies; Communication; Complication; Critical Illness; Cytometry; Data; Development; Dialysis procedure; Disease; Doctor of Philosophy; Economic Burden; End stage renal failure; Endothelial Cells; Endothelium; Epithelial Cells; Evaluation; Familiarity; Fluid Balance; Foundations; Functional disorder; Future; Genetic Transcription; Glomerular Filtration Rate; Goals; Grant; Health; Homeostasis; Hospitalization; Hypoxia; Image; Immune; Impairment; In Vitro; Incidence; Inflammation; Injury; Injury to Kidney; Intensive Care Units; Intervention; Ischemia; Kidney; Kidney Diseases; Link; Literature; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Endothelium; Macrophage; Manuscripts; Maps; Mediator; Mentors; Microscopy; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Myelogenous; NF-kappa B; Natural regeneration; Optics; Oxygen; PECAM1 gene; Pathogenesis; Patients; Physicians; Population; Process; Protocols documentation; Publishing; Regulation; Renal function; Reperfusion Injury; Reperfusion Therapy; Reporter; Research; Risk; Role; Scientist; Signal Transduction; Supportive care; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Time; Tissues; Training; Translational Research; Tubular formation; United States; United States National Institutes of Health; Validation; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factors; Vascular System; Vascular remodeling; Work; Writing; career; career development; cell type; clinical application; clinical care; density; design; doctoral student; experience; experimental study; improved; improved outcome; in vivo; injured; insight; ischemic injury; lymphatic vasculature; lymphatic vessel; mortality; new therapeutic target; next generation sequencing; novel; prevent; progenitor; receptor; renal damage; research and development; response; response to injury; responsible research conduct; skill acquisition; skills; success; targeted treatment; trafficking; transcription factor; transcriptomics

PROJECT SUMMARY: This NIH F30 application describes plan for mentored research and career development for the PI, Gelare Ghajar-Rahimi. The scientific premise of this proposal is focused on the response of the kidney endothelial system to acute kidney injury (AKI), a major complication in up to 20% of hospitalized and 60% of critically ill patients. Despite the high mortality rate and incidence, targeted therapies to treat AKI have not been successfully developed. Homeostasis of lymphatic and blood endothelial cells is vital to maintaining kidney health and influences AKI pathogenesis. In response to injury, kidney lymphatic vessels (LV) undergo a process of expansion termed lymphangiogenesis (LA) that mitigates kidney damage; density of peritubular blood capillaries decreases, contributes to sustained hypoxia and impairs kidney function. Enhancing LA while simultaneously impeding peritubular capillary rarefaction therefore holds immense promise as a therapeutic approach. These two populations have never been studied concurrently in the context of AKI, limiting our ability to develop endothelia-modulating therapies. Here, I aim to elucidate the cellular origins of de novo LA and the mechanisms governing the endothelial remodeling following AKI. My preliminary data and existing literature suggest that 1) de novo LA arises from a progenitor population of pre-existing lymphatic endothelial cells (rather than myeloid- lineage as some older studies posit) and 2) the divergent responses of blood and lymphatic endothelial populations to injury may be explained by the influence of NF-kB signaling within injured proximal tubule cells. My central hypothesis is that that damaged proximal tubules, through NF-kB signaling, promote transcriptional changes in endothelial cells that contribute to lymphatic expansion and vascular rarefaction. I will test this hypothesis through advanced microscopy and single cell transcriptomics and a variety of in vitro and in vivo experiments, including the use of an inducible lymphatic reporter mouse and mice deficient in NF-kB expression in proximal tubules. These findings will significantly advance our understanding of the mechanisms by which kidney endothelial populations respond to injury and could establish NF-kB as a novel therapeutic target in AKI. The proposed training plan for the PI is sponsored by co-mentors Anupam Agarwal, MD, and James George, PhD. Included in the training plan are experiences that will help Gelare develop in three major areas: 1) rigorous lymphatic and kidney research, which includes developing familiarity with the existing literature, critical evaluation of data, and training in the responsible conduct of research; 2) rigorous training in advanced bioinformatics and next-generation sequencing analysis and 3) career and professional development, including grant and manuscript writing, scientific communications, and the translation of research findings to clinical applications. This proposal drives the development of skills required for rigorous scientific research, critical molecular biology and advanced bioinformatics skills necessary for the PI’s future career as a physician-scientist focused on cellular and molecular mechanisms of disease.

项目摘要：此 NIH F30 申请描述了指导研究和职业发展的计划 对于 PI，Gelare Ghajar-Rahimi，该提案的科学前提集中在肾脏的反应上。 内皮系统导致急性肾损伤 (AKI)，这是高达 20% 的住院患者和 60% 的住院患者的主要并发症 尽管死亡率和发病率很高，但治疗 AKI 的靶向疗法尚未出现。 淋巴管和血液内皮细胞的稳态对于维持肾脏健康至关重要。 并影响 AKI 发病机制 为了应对损伤，肾脏淋巴管 (LV) 会经历一个过程： 称为淋巴管生成 (LA) 的扩张可减轻肾小管周围毛细血管的密度； 减少，导致持续缺氧并损害肾功能，同时增强 LA。 因此，阻止管周毛细血管稀疏作为一种治疗方法具有巨大的前景。 从未在 AKI 背景下同时研究两个人群，限制了我们开发的能力 在这里，我的目的是阐明 de novo LA 的细胞起源及其机制。 我的初步数据和现有文献表明 1) de novo LA 源自预先存在的淋巴内皮细胞（而不是骨髓细胞）的祖细胞群。 一些较早的研究提出的谱系）和 2）血液和淋巴内皮细胞的不同反应 群体受到损伤可能是由于损伤的近端小管细胞内 NF-kB 信号传导的影响所致。 我的中心假设是，受损的近端小管通过 NF-kB 信号传导促进转录 内皮细胞的变化导致淋巴管扩张和血管稀疏，我将对此进行测试。 通过先进的显微镜和单细胞转录组学以及各种体外和体内的假设 实验，包括使用诱导性淋巴报告小鼠和缺乏 NF-kB 表达的小鼠 这些发现将显着增进我们对近端小管机制的理解。 肾内皮细胞群对损伤有反应，可以将 NF-kB 确立为 AKI 的新治疗靶点。 拟议的 PI 培训计划由联合导师 Anupam Agarwal（医学博士）和 James George 赞助， 博士培养计划中包括有助于 Gelare 在三个主要领域发展的经验：1）严谨。 淋巴和肾脏研究，包括熟悉现有文献、批判性评估 数据，以及负责任的研究行为的培训；2）高级生物信息学和 下一代测序分析和 3) 职业和专业发展，包括资助和 手稿写作、科学交流以及将研究成果转化为临床应用。 该提案推动了严谨科学研究、关键分子生物学所需技能的发展 以及 PI 未来作为医师科学家的职业所需的高级生物信息学技能，重点关注 疾病的细胞和分子机制。