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
基本信息
- 批准号:10666292
- 负责人:
- 金额:$ 50万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3-DimensionalAcademiaAddressAdipose tissueAffectAntisense OligonucleotidesBrainCardiac MyocytesCardiovascular DiseasesCell Culture TechniquesCellsCentral obesityChronic Kidney FailureCirrhosisClinicCollaborationsCollagenComplexDataDepositionDevelopmentDiabetes MellitusDietDiseaseDisease OutcomeDisease ProgressionFibrosisFoundationsFunctional disorderFutureGene ExpressionGenesGoalsHealthHealth Care CostsHepaticHepatocyteHumanHyperphagiaImmune systemIndustryInflammationInsulin ResistanceKidneyKidney DiseasesLinkLiverLongevityMXI1 geneMalignant neoplasm of liverMediatingMetabolicMetabolic syndromeMissionModelingMusMutationNon-Insulin-Dependent Diabetes MellitusObesityOperative Surgical ProceduresOrganPathway interactionsPatientsPharmacologic SubstancePhenotypePlayPopulationPre-Clinical ModelPreventionPrimary carcinoma of the liver cellsProtein FamilyProteinsProteinuriaReportingRiskRoleSeveritiesSignal TransductionSystemTP53 geneTestingTherapeuticTranslatingTreatment EfficacyUBD proteinUbiquitin Like ProteinsUbiquitinationUnited States National Institutes of HealthValidationXenograft Modelcardiovascular disorder riskchronic liver diseasechronic liver inflammationcomorbiditydisease phenotypeefficacy evaluationfatty liver diseasehepatocellular carcinoma cell linehigh riskhuman diseaseimprovedkidney fibrosislifestyle interventionliver injuryliver transplantationmembermicrobiomemortalitymortality riskmouse modelnew therapeutic targetnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelnovel therapeuticspre-clinicalpreventprotein aggregationside effecttargeted agenttargeted treatmenttherapeutic evaluationtherapeutic targettranslational studytumortumor xenograftwestern diet
项目摘要
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.
摘要:
非酒精性脂肪性肝炎(NASH)是非酒精性脂肪性肝病(NAFLD)的一种晚期形式,是
肝硬化和肝细胞癌(HCC)的主要原因。目前还没有批准的治疗方法,
NASH和晚期纤维化患者因心血管疾病(CVD)而死亡的风险最高。
此外,NAFLD的存在使慢性肾脏疾病(CKD)的风险增加约80%。不
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及其相关合并症(如CKD和CVD)的治疗靶点
在临床上会有很大的益处。
我们发现,在NASH肝脏(主要在肝细胞中)、HCC和HCC中,
CKD小鼠的肿瘤和肾脏。有趣的是,最近发现UBD是六种进展相关的疾病之一。
在NAFLD进展中起重要作用并与脂肪变性、气球样变
炎症、纤维化和NAS评分。类似地,多个报告将肾脏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,
p53、p62和MAD 2,但其在NASH/HCC和CKD中作用的确切机制仍不清楚。没有
UBD(在Ubd-/-小鼠中)改善了整体代谢健康并延长了小鼠寿命。尽管所有的
令人信服的证据表明,UBD尚未被测试为NASH和CKD的治疗靶点。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的治疗方法。我们有
已经开发了一种“GalNAc”缀合的阿索,其在抑制UBD基因表达方面是有效的。
肝细胞我们的初步数据表明,抗UBD GalNAc-ASO显著改善NASH,
纤维化据我们所知,UBD通路尚未被研究其治疗潜力
也不是任何产业界和学术界当前关注的焦点。因此,UBD是一个新的靶点,
提供具有改善NASH和CKD的潜力的新型治疗先导物。
我们将利用饮食诱导NASH的独特临床前小鼠模型,
慢性肾脏病和心血管疾病,后期死亡率(在我们的实验室中建立)。我们将讨论是否反欠发达的ASO
可以改善所有三种疾病的结局沿着生存获益。我们将补充这一模式,
NASH、HCC和CKD的其他临床前模型。以下2个具体目标将在本报告中讨论
提案:目标1将确定UBD抑制是否可预防NASH及其进展为肝硬化,
HCC。此外,我们将使用人原代细胞衍生的3-D球体细胞将我们的发现转化为人类
cultures.目的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。成功完成拟议的目标将建立UBD作为一个新的
NASH和CKD的治疗靶点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Debanjan Dhar其他文献
Debanjan Dhar的其他文献
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{{ truncateString('Debanjan Dhar', 18)}}的其他基金
Dissecting the Intracellular and Extracellular Role of TREM2 in the Pathogenesis of Non-Alcoholic Steatohepatitis.
剖析 TREM2 在非酒精性脂肪性肝炎发病机制中的细胞内和细胞外作用。
- 批准号:
10720352 - 财政年份:2023
- 资助金额:
$ 50万 - 项目类别:
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