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：该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。该提议的科学前提集中在肾脏的反应上 急性肾脏损伤的内皮系统（AKI），高达20％的住院和60％的主要并发症 重病患者。尽管死亡率和事件高，但治疗AKI的有针对性疗法尚未是 成功发展。淋巴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发病机理。为了应对伤害，肾脏淋巴视频（LV）经历了 膨胀称为淋巴管生成（LA），可减轻肾脏损伤；周围血液毛细血管的密度 爆炸，导致持续的缺氧并损害肾脏功能。同时增强洛杉矶 因此，阻碍周围的毛细血管稀疏性作为治疗方法具有巨大的希望。这些 在AKI的背景下，从未同时研究两个人群，从而限制了我们发展的能力 内皮调节疗法。在这里，我的目标是阐明从头洛杉矶的细胞起源和机制 AKI之后，管理内皮重塑。我的初步数据和现有文献表明1） 从头开始是由曾有淋巴内皮细胞的祖细胞种群（而不是髓样 - 谱系作为一些较旧的研究为阳性）和2）血液和淋巴内皮的不同反应 受伤的代理管细胞中NF-KB信号传导的影响可以解释受伤的种群。 我的中心假设是，通过NF-KB信号传导损坏的近端管 内皮细胞的变化有助于淋巴扩张和血管稀疏。我会测试这个 通过晚期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，包括使用诱导型淋巴报告小鼠和缺乏NF-KB表达的小鼠 在近端管中。这些发现将大大提高我们对所采用的机制的理解 肾脏内皮人群对损伤做出反应，并可以将NF-KB确立为AKI的新型治疗靶标。 PI的拟议培训计划由医学博士Anupam Agarwal和James George赞助。 博士学位。培训计划中包括的经验将有助于在三个主要领域发展：1）严格 淋巴研究和肾脏研究，其中包括对现有文献的熟悉，批判性评估 数据，负责任进行研究的培训； 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，包括赠款和 手稿写作，科学沟通以及将研究结果转化为临床应用。 该建议推动了严格的科学研究所需的技能的发展，关键的分子生物学 以及PI作为身体科学家的未来职业所必需的高级生物信息学技能，专注于 疾病的细胞和分子机制。