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：这个NIH F30应用程序描述了指导研究和职业发展计划 私人侦探盖勒·加杰尔·拉希米的这个建议的科学前提是关注肾脏的反应 急性肾损伤（阿基）是20%住院患者和60% 危重病人。尽管死亡率和发病率很高，但治疗阿基的靶向治疗尚未得到广泛应用。 成功开发。淋巴和血液内皮细胞的稳态对维持肾脏健康至关重要 并影响阿基发病机制。在对损伤的反应中，肾淋巴管（LV）经历一个过程， 称为淋巴管生成（LA）的扩张，可减轻肾损伤;肾小管周围毛细血管密度 减少，导致持续缺氧和损害肾功能。增强LA，同时 因此，阻止管周毛细血管稀疏作为治疗方法具有巨大的前景。这些 从未在阿基背景下同时研究过两个人群，这限制了我们开发AKI的能力。 内皮调节疗法。在这里，我的目的是阐明新生LA的细胞起源和机制， 控制阿基后的内皮重塑。我的初步数据和现有文献表明，1） 新生LA产生于预先存在的淋巴管内皮细胞的祖细胞群（而不是髓样的， 和2）血液和淋巴管内皮细胞的不同反应 细胞群对损伤的影响可以通过损伤的近端小管细胞内NF-kB信号传导的影响来解释。 我的中心假设是，受损的近端小管，通过NF-κ B信号，促进转录 导致淋巴管扩张和血管稀疏的内皮细胞变化。我来测试一下 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研究， 实验，包括使用诱导型淋巴报告小鼠和NF-kB表达缺陷小鼠 在近端小管。这些发现将大大促进我们对这些机制的理解， 肾内皮细胞群对损伤有反应，可以将NF-κ B作为阿基的新治疗靶点。 PI的拟议培训计划由共同导师Anupam Agarwal，MD和James乔治赞助， PhD.培训计划中包括的经验将帮助Gelare在三个主要领域发展：1）严格的 淋巴和肾脏研究，包括熟悉现有文献，批判性评价 2）严格的高级生物信息学培训， 下一代测序分析和3）职业和专业发展，包括赠款和 论文写作、科学交流以及将研究成果转化为临床应用。 这项建议推动了严格的科学研究，关键分子生物学所需的技能的发展 和先进的生物信息学技能所必需的PI的未来职业生涯作为一个物理学家，科学家专注于 疾病的细胞和分子机制。