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Principal Investigator: Virender Kumar
Organization: UNIVERSITY OF NEBRASKA MEDICAL CENTER
Fiscal Year: 2021
Award: $105,638
Funding agency: National Institute on Alcohol Abuse and Alcoholism
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.
Terms: <4-Nitrophenol-2-Hydroxylase><AKT><AKT inhibition><Absolute ethanol><Acetaldehyde><Akt protein><Alcohol Chemical Class><Alcohol abuse><Alcoholic Hepatitis><Alcoholic Liver Diseases><Alcohols><Amphoterin><Area><Award><Binding><Biodistribution><Blood><Blood Reticuloendothelial System><CD140b Antigens><CPE1><CYP 2E1><CYP IIE1><CYP2E><CYP2E1><CYP2E1 gene><CYPE1><CYPIIE1><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell Survival><Cell Viability><Cell-Extracellular Matrix><Cells><Cessation of life><Chromosomal Protein, Nonhistone, HMG1><Cirrhosis><Cleaved cell><Collaborations><Cytochrome P-450 CYP2E1><Cytochrome P-450 IIE1><Cytochrome P-450-J><Cytochrome P450 2E1><Cytochrome P450, Family 2, Subfamily E, Polypeptide 1><Cytochrome P450, subfamily Ethanol-Inducible, Polypeptide 1><DNA Damage><DNA Injury><Data><Death><Deposit><Deposition><Development><Diagnosis><Diet><Dimethylnitrosamine N-Demethylase><Disease><Disease Progression><Disease regression><Disorder><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drugs><ECM><ETOH><Encapsulated><Environment><Erinaceidae><Esteroproteases><EtOH abuse><Ethanal><Ethanol><Ethanol-Inducible P450><Ethanol-induced hepatitis><Ethyl Alcohol><Extracellular Matrix><FM1 Gene Product><Faculty><Fats><Fatty Acids><Fatty acid glycerol esters><Fibroblasts><Fibrosis><Funding><GLI Family Protein><GLI Protein><GLI gene><GLI1><GLI1 Gene><GLI1 Protein><Gene Family><Genes><Glioma Associated Oncogene Homolog 1 Protein><Glioma Associated Oncogene Homolog Protein><Glioma-Associated Oncogene Homolog><Goals><Grain Alcohol><Grant><HCV therapy><HCV treatment><HMG-1><HMG-1 Protein><HMG1><HMG3><HMGB1 Protein><Hedgehog (Hh) signal transduction pathway><Hedgehogs><Heparin-Binding Protein p30><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatic Stellate Cell><Hepatic Transplantation><Hepatitis C Therapeutics><Hepatitis C Therapy><Hepatitis C Virus Treatment><Hepatitis C treatment><Hepatocyte><High Mobility Group Box Protein 1><High Mobility Group Protein 1><High-Mobility Group (Nonhistone Chromosomal) Protein 1><High-Mobility Group Box 1><Homolog of Drosophila TOLL><Human><Hydrophobicity><Immune response><Immunoglobulin Enhancer-Binding Protein><Immunological response><In Vitro><Industry><Inflammation><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Inflammatory Response><Injury to Liver><Intestinal Leakage><Intracellular Communication and Signaling><Investigators><Ito Cell><Knowledge><Kupffer Cells><Leadership><Leaky Gut><Ligands><Lipid Peroxidation><Lipids><Lipopolysaccharides><Liver><Liver Cells><Liver Fibrosis><Liver Grafting><Liver Transplant><Liver diseases><Malignant Pancreatic Neoplasm><Malignant neoplasm of pancreas><Mediating><Medication><Mentors><Methylcarbinol><Mice><Mice Mammals><Modern Man><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><N-Nitrosodimethylamine Demethylase><NF-kB><NF-kappa B><NF-kappaB><NFKB><Nature><Necrosis><Necrotic><Nonhistone Chromosomal Protein HGM1><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Oxides><P450-2E1><P450-J><P450C2E><PDGF><PDGF Receptor β><PDGF beta Receptor><PDGF β Receptor><PDGFR beta><PDGFR-β><PI-3K/AKT><PI3K/AKT><Pancreas Cancer><Pancreatic Cancer><Pathogenesis><Pathway interactions><Patients><Peptidases><Peptide Hydrolases><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Platelet-Derived Growth Factor><Platelet-Derived Growth Factor Receptor Beta Polypeptide><Platelet-Derived Growth Factor Receptor β><Platelet-Derived Growth Factor beta Receptor><Pneumonitis><Production><Protease Gene><Proteases><Protein Kinase B><Protein-Serine Kinase><Protein-Serine-Threonine Kinases><Protein-Threonine Kinase><Proteinases><Proteins><Proteolytic Enzymes><Proto-Oncogene Proteins c-akt><Public Health><Pulmonary Inflammation><RAC-PK protein><Recombinants><Research><Research Personnel><Researchers><Role><SBP-1><Sampling><Scientist><Serine Kinase><Serine-Threonine Kinases><Serine/Threonine Protein Kinase Gene><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stellate Sinusoidal Macrophage><Students><Subfamily Ethanol-Inducible Cytochrome P450><Subfamily IIE Cytochrome P450><Sulfoglucuronyl Carbohydrate Binding Protein><Surface><TLR4><TLR4 gene><Threonine Kinase><Toll Homologue><Training><Transcription Activator><Transcription Coactivator><Transcription Factor Coactivator><Transcription Factor NF-kB><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Treatment Efficacy><United States><Up-Regulation><Upregulation><Wound Repair><Writing><abstaining from alcohol><abstaining from ethanol><abstinence from alcohol><abstinence from ethanol><alcohol abstinence><alcohol abuse therapy><alcohol abuse treatment><alcohol co-abuse><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol problem><alcohol treatment><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcoholic liver injury><amphiphilicity><base><biological signal transduction><c myc><c-akt protein><c-myc Genes><career><career development><cell transformation><chronic liver injury><cirrhotic><cleaved><cmyc><conventional therapy><conventional treatment><cytokine><developmental><diet control><dietary control><diets><drug/agent><ethanol abstinence><ethanol abuse><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><experience><fibroblast activating factor><fibroblast activation protein><fibroblast proliferation factor><fibroblast-activating factor><fibrotic liver><gene function><hazardous alcohol use><hedgehog signaling><hedgehog signaling pathway><hepatic body system><hepatic damage><hepatic disease><hepatic fibrosis><hepatic injury><hepatic organ system><hepatopathy><hh signaling pathway><host response><immune system response><immunoresponse><in vivo><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><intervention efficacy><kappa B Enhancer Binding Protein><kidney fibrosis><liver damage><liver disorder><liver inflammation><liver injury><liver macrophage><liver transplantation><member><nano carrier><nano medicinal><nano medicine><nano particle><nano-sized particle><nanocarrier><nanomedicinal><nanomedicine><nanoparticle><nanosized particle><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><nuclear factor kappa beta><overexpress><overexpression><pancreatic malignancy><pathway><prevent><preventing><problem alcohol use><problem drinking><problematic alcohol consumption><problematic alcohol use><protein expression><proto-oncogene protein RAC><proto-oncogene protein akt><rac protein kinase><related to A and C-protein><renal fibrosis><response><skills><smoothened signaling pathway><social role><tenure process><tenure track><therapeutic efficacy><therapy efficacy><toll-like receptor 4><transcription co-activator><transcriptional co-activator><transformed cells><v-myc Avian Myelocytomatosis Viral Oncogene Cellular Homolog><wound healing><wound resolution>