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Gene Nutrient Interactions in Kidney Function

肾功能中的基因营养相互作用

基本信息

批准号：
10676812
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
项目类别：
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/10676812
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 pharmacologic pup retinoic acid receptor alpha retinoic acid receptor gamma success tool toxicant

项目摘要

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 syndromes that are quite common in the USA. CKD 影响着世界 10% 以上的人口 is an increasing global health burden. The prevalence of CKD in the USA is ~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 disease, and toxicants are less common causes. Both AKD and CKD are associated with major cardiovascular complications.因此，CKD 的新疗法和对 CKD 的更深入了解 genesis of CKD are greatly needed. Vitamin A (all-trans retinol, VA), a micronutrient and essential vitamin 生命所必需的物质只能从我们的饮食中获取。 Vitamin A (retinol) is required for kidney development, but much less is known about the functions of this important micronutrient, vitamin A, in 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 protective role against CKD and that a RARβ2 selective agonist could inhibit the development of CKD 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 expand our research into new, but complementary directions. Our hypothesis for Aim (1) is that the 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， has key actions in multiple, different cell types in the adult kidney and that mice deficient in RARs in specific kidney 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 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 不同的鼠标型号。 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.