Ubiquitin D as a potential therapeutic target for NASH, HCC and chronic kidney diseases

泛素 D 作为 NASH、HCC 和慢性肾脏疾病的潜在治疗靶点

• 批准号: 10666292
• 负责人: Debanjan Dhar
• 金额: $ 50万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666292
• 关键词: 3-Dimensional; Academia; Address; Adipose tissue; Affect; Antisense Oligonucleotides; Brain; Cardiac Myocytes; Cardiovascular Diseases; Cell Culture Techniques; Cells; Central obesity; Chronic Kidney Failure; Cirrhosis; Clinic; Collaborations; Collagen; Complex; Data; Deposition; Development; Diabetes Mellitus; Diet; Disease; Disease Outcome; Disease Progression; Fibrosis; Foundations; Functional disorder; Future; Gene Expression; Genes; Goals; Health; Health Care Costs; Hepatic; Hepatocyte; Human; Hyperphagia; Immune system; Industry; Inflammation; Insulin Resistance; Kidney; Kidney Diseases; Link; Liver; Longevity; MXI1 gene; Malignant neoplasm of liver; Mediating; Metabolic; Metabolic syndrome; Mission; Modeling; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Organ; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Play; Population; Pre-Clinical Model; Prevention; Primary carcinoma of the liver cells; Protein Family; Proteins; Proteinuria; Reporting; Risk; Role; Severities; Signal Transduction; System; TP53 gene; Testing; Therapeutic; Translating; Treatment Efficacy; UBD protein; Ubiquitin Like Proteins; Ubiquitination; United States National Institutes of Health; Validation; Xenograft Model; cardiovascular disorder risk; chronic liver disease; chronic liver inflammation; comorbidity; disease phenotype; efficacy evaluation; fatty liver disease; hepatocellular carcinoma cell line; high risk; human disease; improved; kidney fibrosis; lifestyle intervention; liver injury; liver transplantation; member; microbiome; mortality; mortality risk; mouse model; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; pre-clinical; prevent; protein aggregation; side effect; targeted agent; targeted treatment; therapeutic evaluation; therapeutic target; translational study; tumor; tumor xenograft; western diet

Abstract: Non-alcoholic steatohepatitis (NASH), an advanced form of non-alcoholic fatty liver disease (NAFLD), is one of the major causes of cirrhosis and hepatocellular carcinoma (HCC). There is currently no approved treatment for NASH and patients with advanced fibrosis are at highest risk of mortality due to cardiovascular diseases (CVD). Furthermore, presence of NAFLD increases the risk of chronic kidney disease (CKD) by about 80%. It is not known how NASH and CKD influence each other, but together they can influence CVD and patient mortality. Therefore, a therapeutic target that can improve NASH and its associated co-morbidities such as CKD and CVD will be of great benefit in clinics. We found that Ubiquitin D (UBD) is highly upregulated in NASH livers (primarily in the hepatocytes), HCC tumors and kidneys of CKD mice. Interestingly, UBD was recently found to be one of the six progression-related genes that play a vital role in the progression of NAFLD and positively correlates with steatosis, ballooning, inflammation, fibrosis and NAS score. Similarly, multiple reports link renal UBD to proteinuria and kidney disease. UBD is known to participate in alternative ubiquitination pathway and interact with key cellular proteins such as p53, p62 and MAD2 but the precise mechanism of its role in NASH/HCC and CKD remains unclear. Absence of UBD (in Ubd-/- mice) improved overall metabolic health and extended the mouse lifespan. Despite all the compelling evidences, UBD has not been tested as a therapeutic target for NASH and CKD. Here, we propose to suppress UBD using anti-sense oligos (ASOs) as a therapeutic approach to treat NASH and CKD. We have already developed a “GalNAc” conjugated ASO that is potent in suppressing UBD gene expression in the hepatocytes. Our preliminary data indicates that anti-UBD GalNAc-ASO significantly improved NASH and fibrosis. According to our knowledge, UBD pathway has not been investigated for its therapeutic potential before and also is not a current focus of any industry or academia. Therefore, UBD is a novel target and anti-UBD ASOs provide novel therapeutic leads with a potential to improve both NASH and CKD. We will take advantage of a unique pre-clinical mouse model of diet-induced NASH that also develop CKD and CVD with mortality at later stages (established in our lab). We will address whether anti-UBD ASOs could improve all three disease outcome along with survival benefit. We will supplement this model with additional preclinical models of NASH, HCC and CKD. The following 2 Specific Aims will be addressed in this proposal: Aim 1 will Identify whether UBD suppression prevents NASH and its progression to Cirrhosis and HCC. Additionally, we will translate our findings to human using human primary cell derived 3-D spheroid cell cultures. Aim 2 will investigate the effect of UBD suppression on CKD, CVD and survival benefit either in the context of NASH and/or CKD. Successful completion of the proposed aims will establish UBD as a novel therapeutic target for NASH and CKD.

抽象的： 非酒精性脂肪性肝炎（NASH）是非酒精性脂肪性肝病（NAFLD）的一种高级形式，是一种 肝硬化和肝细胞癌（HCC）的主要原因。目前尚无批准的治疗方法 NASH 和晚期纤维化患者因心血管疾病 (CVD) 死亡的风险最高。 此外，NAFLD 的存在会使慢性肾病 (CKD) 的风险增加约 80%。它不是 我们知道 NASH 和 CKD 如何相互影响，但它们共同影响 CVD 和患者死亡率。 因此，可以改善 NASH 及其相关并发症（如 CKD 和 CVD）的治疗靶点 将在临床上大有裨益。 我们发现泛素 D (UBD) 在 NASH 肝脏（主要在肝细胞）、HCC 中高度上调 CKD 小鼠的肿瘤和肾脏。有趣的是，最近发现 UBD 是六种与进展相关的疾病之一 这些基因在 NAFLD 的进展中发挥着至关重要的作用，并与脂肪变性、气球样变、 炎症、纤维化和 NAS 评分。同样，多项报告将肾 UBD 与蛋白尿和肾脏疾病联系起来。 已知 UBD 参与替代泛素化途径并与关键细胞蛋白相互作用，例如 p53、p62 和 MAD2，但其在 NASH/HCC 和 CKD 中作用的确切机制仍不清楚。不存在 UBD（在 Ubd-/- 小鼠中）改善了整体代谢健康并延长了小鼠的寿命。尽管所有的 令人信服的证据表明，UBD 尚未作为 NASH 和 CKD 的治疗靶点进行过测试。在此，我们建议 使用反义寡核苷酸 (ASO) 抑制 UBD 作为治疗 NASH 和 CKD 的方法。我们有 已经开发出一种“GalNAc”缀合 ASO，可有效抑制 UBD 基因表达 肝细胞。我们的初步数据表明，抗 UBD GalNAc-ASO 显着改善了 NASH 和 纤维化。据我们所知，UBD 通路之前尚未对其治疗潜力进行过研究 并且也不是任何行业或学术界当前关注的焦点。因此，UBD 是一个新的靶点和抗 UBD ASO 提供新的治疗线索，有可能改善 NASH 和 CKD。 我们将利用饮食诱导 NASH 的独特临床前小鼠模型，该模型也能开发 CKD 和 CVD 晚期死亡（在我们实验室建立）。我们将讨论是否存在反 UBD ASO 可以改善所有三种疾病的结果以及生存获益。我们将补充这个模型 NASH、HCC 和 CKD 的其他临床前模型。本计划将解决以下 2 个具体目标 提案：目标 1 将确定 UBD 抑制是否可以预防 NASH 及其进展为肝硬化和 肝癌。此外，我们将使用人类原代细胞衍生的 3-D 球状细胞将我们的发现转化为人类 文化。目标 2 将研究 UBD 抑制对 CKD、CVD 和生存获益的影响 NASH 和/或 CKD 的背景。成功完成拟议目标将使 UBD 成为一个新颖的 NASH 和 CKD 的治疗靶点。