Targeting PI3K/BRD4 and Hedgehog Pathway in Alcohol Associated Liver Disease
靶向 PI3K/BRD4 和 Hedgehog 通路治疗酒精相关性肝病
基本信息
- 批准号:10686248
- 负责人:
- 金额:$ 10.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-22 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AKT inhibitionAbbreviationsAcetaldehydeAlcohol abuseAlcoholic HepatitisAlcoholic Liver DiseasesAlcoholsAreaAwardBindingBiodistributionBloodCYP2E1 geneCell SurvivalCellsCessation of lifeCirrhosisCollaborationsCommunicationCredentialingDNA DamageDataDepositionDevelopmentDiagnosisDietDiseaseDisease ProgressionDisease regressionDrug Delivery SystemsDrug KineticsEncapsulatedEnvironmentErinaceidaeEthanolExtracellular MatrixFacultyFatty AcidsFatty acid glycerol estersFibroblastsFibrosisFundingGLI Family ProteinGLI geneGene FamilyGenesGoalsGrantHMGB1 geneHepatic Stellate CellHepatocyteHumanHydrophobicityImmune responseIn VitroIndustryInflammationInflammatoryInflammatory Bowel DiseasesInflammatory ResponseKnowledgeKupffer CellsLeadershipLeaky GutLigandsLipid PeroxidationLipidsLipopolysaccharidesLiverLiver FibrosisLiver diseasesMalignant neoplasm of pancreasMediatingMentorsMorbidity - disease rateMusNF-kappa BNanosphereNatureNecrosisPI3K/AKTPIK3CG genePathogenesisPathway interactionsPatientsPeptide HydrolasesPeptidesPharmaceutical PreparationsPlatelet-Derived Growth FactorPlatelet-Derived Growth Factor beta ReceptorProductionProductivityProtein-Serine-Threonine KinasesProteinsProto-Oncogene Proteins c-aktPublic HealthPulmonary InflammationRecombinantsResearchResearch PersonnelRoleSamplingScientistSerineSignal PathwaySignal TransductionStudentsSurfaceTLR4 geneTrainingTranscription CoactivatorTreatment EfficacyUnited StatesUp-RegulationWritingalcohol abstinencec-myc Genescareercareer developmentcell transformationchronic liver injuryconventional therapycytokinedietary controlexperiencefibroblast activation protein alphafibroblast-activating factorin vivoinhibitorinnovationkidney fibrosisliver inflammationliver injuryliver transplantationmembermultidisciplinarynanocarriernanomedicinenanoparticlenew therapeutic targetnext generationnovelnovel therapeuticsoverexpressionpeptide amphiphilespreventprotein expressionresponseself assemblyskillssmoothened signaling pathwaysynergismtenure trackwound healing
项目摘要
PROJECT SUMMARY
This K01 application aims to promote the applicant's development to become a multi-disciplinarily trained and
independent academic researcher. This application's collective strengths are defined in these 3 major areas: 1)
Credentials: PI's application builds upon his productive track-record to achieve scientific independence in the
field of drug delivery and liver fibrosis, including alcohol-associated liver disease (AALD). The PI's goals include
enhancing grantsmanship, leadership, and team management skills to become an independent, tenure-track
academic researcher. In addition to technical training, PI intends to build skills in communicating with faculty
members, industry members, and students. 2) Training Environment: Drs. Mahato (mentor) and Kharbanda, and
Cheng (co-mentors) are world-class researchers and fully committed to advancing the PI's career. Particular
emphasis will be given to grant writing, collaboration building, and applying for external funding. The mentoring
committee has strong credentials in developing the next generation of successful academic scientists. The
knowledge and experience gained during this award period will help the candidate generate data to apply for an
R21/R01 grant. 3) Innovative Research: PI's central hypothesis is that alcohol-induced activation of inflammatory
pathways is mediated by AKT and BRD4 and synergize with the hedgehog (Hh) pathway to promote AALD.
Simultaneous inhibition of these pathways using targeted nanomedicine could alleviate the progression of AALD
and related morbidities. The PI has generated the following preliminary results; (a) Conditioned media from the
EtOH treated primary human hepatocytes significantly stimulated hepatic stellate cells (HSCs) as determined by
α-SMA expression levels and upregulated GLI1/2 activity; (b) The protein cMYC is upregulated in patient
samples diagnosed with alcoholic hepatitis; (c) Treatment with novel inhibitors MDB5 (Hh) and SF2523
(PI3K/BRD4) showed decreased their target genes in HSC-T6 cells; (d) EtOH diet-fed mice show increased p-
AKT, cMYC, and GLI1/2 protein levels in the liver compared to mice on the control diet; (e) Treatment with
MDB5 and SF2523 decreased liver injury markers ALT and AST, and lowered GLI1, cMYC, and p-AKT protein
levels in ethanol-fed mice; (f) Novel cleavable amphiphilic peptide (CAP) was self-assembled into nanoparticles
(NPs) of size range 100± 10 nm loaded with both the drugs (payload 5% w/w); (g) CAP-NPs were sensitive to
fibroblast activation protein (FAP-α), and NPs dissembled in presence of recombinant FAP-α. Based on these
robust results, the proposal has the following specific aims: Aim 1. Establish the role of AKT/BRD4 dual inhibitor
SF2523 and Hh inhibitor MDB5 in AALD. Aim 2. Formulate and characterize HSC targeted CAP-NP loaded
with SF2523 and MDB5. Aim 3. Determine therapeutic efficacy of SF2523 and MDB5 loaded pPB-CAP-NPs in
ALD mice. The new knowledge and nanomedicine generated in this proposal may open new therapeutic avenues
for the treatment of AALD.
项目摘要
此K 01应用程序旨在促进申请人的发展,成为一个多学科的培训,
独立学术研究员。此应用程序的集体优势定义在以下3个主要领域:1)
证书:PI的申请建立在他富有成效的跟踪记录基础上,以实现科学的独立性。
药物递送和肝纤维化领域,包括酒精相关性肝病(AALD)。PI的目标包括
提高granitarian,领导和团队管理技能,成为一个独立的,终身的轨道
学术研究者除了技术培训外,PI还打算培养与教师沟通的技能
会员、行业会员和学生。2)培训环境:Mahato博士(导师)和Kharbanda博士,以及
Cheng(共同导师)是世界级的研究人员,并完全致力于推进PI的职业生涯。特别
重点将放在编写赠款、建立合作和申请外部资金。辅导
委员会在培养下一代成功的学术科学家方面具有很强的资历。的
在此期间获得的知识和经验将帮助候选人生成数据,以申请
R21/R 01赠款。3)创新研究:PI的中心假设是酒精诱导的炎症激活
AALD通路由AKT和BRD 4介导,并与Hh通路协同促进AALD。
使用靶向纳米药物同时抑制这些途径可以缓解AALD的进展
以及相关的疾病PI产生了以下初步结果:(a)来自
EtOH处理的原代人肝细胞显著刺激肝星状细胞(HSC),如通过
α-SMA表达水平和上调的GLI 1/2活性;(B)患者中cMYC蛋白上调
(c)用新型抑制剂MDB 5(Hh)和SF 2523治疗
(PI3K/BRD 4)显示出它们在HSC-T6细胞中的靶基因减少;(d)EtOH饮食喂养的小鼠显示出增加的p-
与对照饮食的小鼠相比,肝脏中的AKT、cMYC和GLI 1/2蛋白水平;
MDB 5和SF 2523降低肝损伤标志物ALT和AST,并降低GLI 1、cMYC和p-AKT蛋白
(f)新型可裂解两亲肽(CAP)自组装成纳米颗粒
(NPs)负载有两种药物的尺寸范围为100± 10 nm(有效载荷5%w/w)的CAP-NP;
成纤维细胞活化蛋白(FAP-α),以及在重组FAP-α存在下分解的NPs。基于这些
为了取得强有力的结果,该提案有以下具体目标:目标1。确定AKT/BRD 4双重抑制剂的作用
SF 2523和Hh抑制剂MDB 5在AALD中的作用。目标2.配制并表征HSC靶向的负载的CAP-NP
SF 2523和MDB 5。目标3.测定SF 2523和MDB 5负载的pPB-CAP-NP在小鼠中的治疗功效。
ALD小鼠。这项提议中产生的新知识和纳米医学可能会开辟新的治疗途径
用于治疗AALD。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Virender Kumar其他文献
Virender Kumar的其他文献
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{{ truncateString('Virender Kumar', 18)}}的其他基金
Phosphodiesterase 4B Inhibition as a Therapeutic Target for Alcohol-associated Liver Disease
磷酸二酯酶 4B 抑制作为酒精相关性肝病的治疗靶点
- 批准号:
10354185 - 财政年份:2023
- 资助金额:
$ 10.56万 - 项目类别:
Targeting PI3K/BRD4 and Hedgehog Pathway in Alcohol Associated Liver Disease
靶向 PI3K/BRD4 和 Hedgehog 通路治疗酒精相关性肝病
- 批准号:
10351877 - 财政年份:2021
- 资助金额:
$ 10.56万 - 项目类别:
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