Gene Nutrient Interactions in Kidney Function

肾功能中的基因营养相互作用

• 批准号: 10444744
• 负责人: LORRAINE J GUDAS
• 金额: $ 41.4万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-04 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444744
• 关键词: Acute; Adult; Advanced Development; Affect; Agonist; Agriculture; All-Trans-Retinol; American; Area; Binding; Biochemical; Bioinformatics; Biology; Cardiovascular system; Cells; Chronic Kidney Failure; Data; Development; Diabetes Mellitus; Diet; Disease; Disease model; Drops; Food Interactions; Funding; Gene Targeting; Genes; Genetic; Genetic Transcription; Glomerulonephritis; Grant; Health; Human; Hypertension; Injury; Injury to Kidney; Kidney; Kidney Diseases; Laboratories; Lead; Life; Manuscripts; Measurement; Medicine; Methods; Micronutrients; Modeling; Molecular; Mothers; Mus; Nephrolithiasis; Nephrons; New York City; Obesity; Pathologic; Pathologist; Pathology; Pharmacology; Play; Polycystic Kidney Diseases; Population; Positioning Attribute; Postdoctoral Fellow; Pregnancy; Prevalence; RARB gene; Receptor Signaling; Renal carcinoma; Renal function; Research; Research Personnel; Retinoic Acid Receptor; Retinoids; Role; Severities; Signal Transduction; Specialist; Syndrome; Testing; Therapeutic; Tretinoin; Vitamin A; Vitamin A Deficiency; Vitamins; body system; cell type; efficacy testing; experience; genetic approach; global health; kidney cell; kidney fibrosis; medical schools; molecular targeted therapies; mouse model; nephrogenesis; novel; novel therapeutic intervention; novel therapeutics; nutrition; pup; retinoic acid receptor alpha; retinoic acid receptor gamma; success; tool; toxicant

Acute kidney disease (AKD) and chronic kidney disease (CKD) are interconnected, pathological syndromes that are quite common in the USA. CKD affects greater than 10% of the world’s population and is an increasing global health burden. The prevalence of CKD in the USA is ~12-14%. Diabetes and hypertension cause ~ two-thirds of CKD cases, while glomerulonephritis, nephrolithiasis, polycystic kidney disease, and toxicants are less common causes. Both AKD and CKD are associated with major cardiovascular complications. Thus, both new treatments for CKD and a deeper understanding of the genesis of CKD are greatly needed. Vitamin A (all-trans retinol, VA), a micronutrient and essential vitamin necessary for life, can only be obtained from our diets. Vitamin A (retinol) is required for kidney development, but much less is known about the functions of this important micronutrient, vitamin A, in the adult kidney. Vitamin A’s metabolites (e.g. retinoic acid (RA)) primarily act by binding to three distinct retinoic acid receptors (RARs) and modifying transcription. In R01 DK113088, a new R01 grant funded in December, 2017, we hypothesized that RARβ played a protective role against CKD and that a RARβ2 selective agonist could inhibit the development of CKD associated with obesity. We have proved these hypotheses and we will build on our exciting results and expand our research into new, but complementary directions. Our hypothesis for Aim (1) is that the RARβ2 selective agonist, AC261066, will be effective in reducing the pathological sequelae after more than one type of kidney injury, not just lipotoxicity-related injury associated with obesity-induced chronic kidney disease. For Aim (2), we hypothesize that vitamin A, via each retinoic acid receptor, including RARγ, which we are just beginning to study, has key actions in multiple, different cell types in the adult kidney and that mice deficient in RARs in specific kidney cells may be models of various human kidney diseases. We propose two specific aims: Specific Aim (1): Because we have evidence that a selective RARβ2 agonist has a therapeutic impact on the development of CKD in one mouse model, we propose to test the efficacy of this RARβ2 agonist in two additional CKD models, potentially creating a rationale to use AC261066 as a lead compound for treatment of CKD and to define its gene targets. Specific Aim (2): Our genetic approach to study the micronutrient vitamin A has been fruitful and has generated several potentially useful models of various types of CKD. Furthermore, our results suggest that the interaction of the kidney with other organ systems varies in different mouse models. Thus, we propose to evaluate the actions of the retinoic acid receptors α, β, and γ in specific cell types in the kidney. We will, through this research, understand the pathologies of CKDs in more depth, elucidate how these pathologies relate to nutrition and aberrant vitamin A signaling, discover new, useful models of CKD, and advance the development of a novel therapeutic for CKD.

急性肾病（AKD）和慢性肾病（CKD）是相互关联的、病理性的 在美国很常见的综合症。 CKD 影响着世界 10% 以上的人口 是日益增加的全球健康负担。在美国，CKD 的患病率约为 12-14%。糖尿病和 约三分之二的 CKD 病例由高血压引起，而肾小球肾炎、肾结石、多囊肾则由高血压引起 疾病和有毒物质是不太常见的原因。 AKD 和 CKD 均与主要疾病相关 心血管并发症。因此，CKD 的新疗法和对 CKD 的更深入了解 CKD 的起源是非常需要的。维生素 A（全反式视黄醇，VA），一种微量营养素和必需维生素 生命所必需的物质只能从我们的饮食中获取。肾脏需要维生素A（视黄醇） 但人们对这种重要的微量营养素维生素 A 的功能知之甚少。 成人的肾脏。维生素 A 的代谢物（例如视黄酸 (RA)）主要通过与三种不同的物质结合来发挥作用 视黄酸受体 (RAR) 和修饰转录。 在 R01 DK113088（2017 年 12 月资助的一项新的 R01 赠款）中，我们假设 RARβ 发挥了 对 CKD 的保护作用以及 RARβ2 选择性激动剂可以抑制 CKD 的发展 与肥胖有关。我们已经证明了这些假设，我们将在我们令人兴奋的结果的基础上继续努力 将我们的研究扩展到新的但互补的方向。我们对目标 (1) 的假设是 RARβ2 选择性激动剂AC261066将有效减少一种以上肾病后的病理后遗症 损伤，而不仅仅是与肥胖引起的慢性肾病相关的脂毒性相关损伤。对于目标（2），我们 假设维生素 A 通过每个视黄酸受体，包括我们刚刚开始研究的 RARγ， 在成人肾脏中多种不同的细胞类型中具有关键作用，并且在特定肾脏中缺乏 RAR 的小鼠 细胞可能是各种人类肾脏疾病的模型。我们提出两个具体目标： 具体目标 (1)：因为 我们有证据表明选择性 RARβ2 激动剂对 CKD 的发展具有治疗作用 在一个小鼠模型中，我们建议测试这种 RARβ2 激动剂在另外两种 CKD 中的功效 模型，可能为使用 AC261066 作为先导化合物治疗 CKD 和 定义其基因目标。具体目标 (2)：我们研究微量营养素维生素 A 的遗传学方法 已经取得了丰硕的成果，并生成了多种潜在有用的各种类型 CKD 模型。 此外，我们的结果表明，肾脏与其他器官系统的相互作用在以下方面有所不同： 不同的鼠标型号。因此，我们建议评估视黄酸受体 α、β 和 肾脏中特定细胞类型中的 γ。我们将通过这项研究了解 CKD 的病理学 更深入地阐明这些病理学与营养和异常维生素 A 信号传导的关系， 发现新的、有用的 CKD 模型，并推动 CKD 新型疗法的开发。