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Role of CARF in Insulin Resistance and Non Alcoholic Fatty Liver disease NAFLD

Award Number: SC2GM125551
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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Role of CARF in Insulin Resistance and Non Alcoholic Fatty Liver disease NAFLD - Project Summary: Obesity is increasing in alarming rate in the USA and more than 70% of obese people suffer from non-alcoholic fatty liver diseases (NAFLD) which turn into hepatocarcinoma (HCC). Smoking is a risk factor for NAFLD and using diet induced obesity (DIO) mice model we demonstrated that nicotine can exacerbate obesity induced NAFLD whose mechanisms are not understood yet. Studies showed that tumor suppressor p53 can play a role in insulin resistance (IR) and progression to NAFLD in DIO mice. The mechanisms of p53 induced IR and NAFLD are largely unknown. CARF (Collaborator of Alternative Reading Frame Protein) is a new member of p53 pathways and we demonstrated that its function is, at least in part, regulated by p53 and an inverse relationship between CARF and p53 determines cellular fate responding to various stresses. Preliminary data showing accumulative effect of nicotine and HFD on oxidative stress and apoptosis and reduction of CARF expression in liver of HFD fed mice suggest its possible role in insulin sensitivity and lipid homeostasis and development of NAFLD. In this study our specific aims are: 1. To show that CARF is necessary and sufficient to maintain insulin sensitivity using in vitro and in vivo models of insulin resistance. 2. To demonstrate if CARF inhibition by p53 causes insulin resistance in mice treated with HFD with and without nicotine. We will create DIO mice model by feeding C57/ BL6 mice on HFD and cellular model of IR by treating HepG2 (hepatic), liver derived hepatocytes, C2C12 (muscle) cell lines with palmitate-BSA conjugate. We will use pfithrin, an inhibitor of p53 or p53 specific siRNA to inactivate p53 in HepG2 cells or p53 knockout mice and will investigate its effect on CARF expression as well as genes related to lipid metabolism, apoptosis upon treated with nicotine and HFD alone or in combination. These results will be further complemented by knocking down or over expressing of CARF both in vivo and in vitro under IR or normal conditions to delineate CARF function in lipid metabolism as well as in NAFLD. From this study, we expect that CARF enhances insulin sensitivity and facilitates fatty acid metabolism and thus protects mice from NAFLD. Besides, CARF may also protect NAFLD by inhibiting p53 -mediated apoptosis. Thus, it can be expected that by uncovering the function of CARF in IR and associated metabolic diseases such as NAFLD this study will open new window for more extensive studies on CARF's role in metabolic diseases. My immediate goal would be using training from SC2 grant and my prior experiences on basic research to become independent and competent faculty at CDU. Eventually this will help me to secure RO1, SC1 and other foundation grants to establish my own research team focusing on IR, obesity, diabetes and NAFLD.


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: 2024 ( Subtotal = $0 )
2024	2021	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	10/24/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $143,500 )
2021	2021	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	12/22/2020	NON-COMPETING CONTINUATION	$129,150
2021	2021	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	001	3	2/17/2021	NON-COMPETING CONTINUATION	$14,350
														Subtotal = $143,500

Issue Date FY: 2020 ( Subtotal = $143,500 )
2020	2020	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	3/3/2020	NON-COMPETING CONTINUATION	$143,500
														Subtotal = $143,500

Issue Date FY: 2019 ( Subtotal = $143,500 )
2019	2019	CHARLES DREW UNIVERSITY OF MEDICINE AND SCIENCE	1621 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	12/26/2018	NEW	$143,500
														Subtotal = $143,500

Grand Total All Awards = $430,500

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Role of CARF in Insulin Resistance and Non Alcoholic Fatty Liver disease NAFLD

Award Number: SC2GM125551

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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