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Targeting PI3K/BRD4 and Hedgehog Pathway in Alcohol Associated Liver Disease

Award Number: K01AA029763
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/11/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Targeting PI3K/BRD4 and Hedgehog Pathway in Alcohol Associated Liver Disease - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Alcohol Research Programs	001	3	2/19/2025	NON-COMPETING CONTINUATION	-$1
2025	2023	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Alcohol Research Programs	002	4	2/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$7,506
2025	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Alcohol Research Programs	000	2	2/19/2025	NON-COMPETING CONTINUATION	-$7,505
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $105,639 )
2024	2024	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Alcohol Research Programs	002	5	7/31/2024	NON-COMPETING CONTINUATION	$105,638
2024	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	3	7/10/2024	NON-COMPETING CONTINUATION	-$105,637
2024	2023	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Alcohol Research Programs	001	4	7/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$105,638
														Subtotal = $105,639

Issue Date FY: 2023 ( Subtotal = $105,638 )
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	3	8/25/2023	NON-COMPETING CONTINUATION	$105,638
														Subtotal = $105,638

Issue Date FY: 2022 ( Subtotal = $105,638 )
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	2	8/18/2022	NON-COMPETING CONTINUATION	$105,638
														Subtotal = $105,638

Issue Date FY: 2021 ( Subtotal = $105,638 )
2021	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	1	9/22/2021	NEW	$105,638
														Subtotal = $105,638

Grand Total All Awards = $422,553

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Targeting PI3K/BRD4 and Hedgehog Pathway in Alcohol Associated Liver Disease

Award Number: K01AA029763

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/11/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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