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.

急性肾脏病（AKD）和慢性肾脏病（CKD）是相互联系的 在美国很常见的综合征。 CKD影响着世界人口的10％以上 是一个日益增长的全球健康伯恩。美国CKD的患病率在美国约12-14％。糖尿病和 高血压导致〜三分之二的CKD病例，而肾小球肾炎，肾结石，多囊肾脏 疾病和毒物是不太常见的原因。 AKD和CKD都与专业有关 心血管并发症。这是CKD的新治疗方法，以及对 CKD的起源非常需要。维生素A（全反射视黄醇，VA），一种微量营养素和必需维生素 生命所需的，只能从我们的饮食中获得。肾脏需要维生素A（视黄醇） 开发，但对这种重要的微量营养素的功能，维生素A的功能知之甚少 成人肾脏。维生素A的代谢产物（例如视黄酸（RA））主要作用与三个不同的不同 视黄酸受体（RARS）和修饰转录。 在R01 DK113088中，2017年12月资助的新R01赠款，我们假设RARβ发挥了 对CKD的保护作用，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，我们将以激动人心的结果为基础 将我们的研究扩展到新的但完整的方向。我们目标的假设是RARβ2 选择性激动剂AC261066将有效减少多种类型的肾脏后遗症 损伤，不仅是与肥胖引起的慢性肾脏疾病有关的脂肪毒性相关损伤。为了目标（2），我们 假设维生素A通过每个视黄酸受体，包括RARγ，我们才刚刚开始研究， 在成年肾脏中具有多种不同细胞类型的关键作用，而在特定肾脏中缺乏ras的小鼠 细胞可能是各种人类肾脏疾病的模型。我们提出了两个具体目标：具体目标（1）：因为 我们有证据表明，选择性RARβ2激动剂对CKD的发展有治疗影响 在一个小鼠模型中，我们建议在另外两个CKD中测试该RARβ2激动剂的效率 模型，有可能建立使用AC261066作为铅化合物的基本原理，以治疗CKD和 定义其基因靶标。特定目的（2）：我们研究微量营养素维生素A的遗传学方法 已经富有成果，已经生成了各种CKD的几种潜在有用的模型。 此外，我们的结果表明，肾脏与其他器官系统的相互作用 不同的鼠标模型。这，我们建议评估视黄酸受体α，β和 肾脏中的γ肾脏类型。通过这项研究，我们将了解CKD的病理 更深入地，阐明了这些病理与营养和异常维生素A信号传导之间的关系， 发现CKD的新型，有用的模型，并推动开发CKD的新疗法。