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Principal Investigator: Kamrul M Hasan
Organization: CHARLES R. DREW UNIVERSITY OF MED & SCI
Fiscal Year: 2024
Award: $144,500
Funding agency: National Institute of General Medical Sciences
Project Summary:
With the dramatic increase in obesity and diabetes, the prevalence of nonalcoholic fatty liver diseases
(NAFLD) is increasing at an alarming rate worldwide. NAFLD is a significant risk factor for insulin
resistance (IR), type 2 diabetes (T2DM), and cardiovascular diseases. We need to understand the underlying
molecular mechanisms adequately to manage NAFLD and T2DM clinically. CARF is a novel p53 pathway
protein that interacts with p53 and regulate its functions. Previous studies reported that an inverse
relationship exists between CARF and p53. We posit that p53-CARF interplay plays a vital role in the
outcome of p53 actions responding to various stressors. Our recent publication showed that free fatty acid
(FFA)-induced stress suppressed hepatic CARF that triggered fat deposition in the liver, while exogenous
delivery of CARF prevented it. Further, we found that silencing of CARF perturbed insulin signaling
pathway in hepatocytes. Most intriguingly, expression of PCK1, a key hepatic gluconeogenic gene, was
increased after silencing of CARF in hepatocytes. This led us to propose that CARF is a transcriptional
regulator of PCK1 and, hence hepatic glucose output and IR. Growing evidence suggests that metabolic
stress-induced p53 could alter the cell's metabolic homeostasis leading to the development of NAFLD and
IR in both humans and rodents. Notably, our preliminary data further showed that CARF expression was
decreased in HFD-fed livers with increased p53, thus establishing an inverse relationship. However, the
role of this inverse relationship in metabolic stress and its outcome are unknown. We hypothesize that
CARF could be a downstream target of p53 in metabolic stress. Its inhibition drives the development of IR
and NAFLD. Using in vitro cellular and in vivo mouse models of NAFLD and IR integrated with the ChIP-
sequencing, CUT and RUN sequencing, Co-IP, ITT, GTT, and PTT assays, this study will uncover a novel
function of CARF -p53 interplay in the development of NAFLD and IR. Understanding this mechanism
could reduce a considerable health burden in the USA and worldwide. This SuRE grant will create an
opportunity for mentoring underserved undergraduate and graduate students to complete their research
thesis at Charles R. Drew University of Medicine and Science. Recent data show that the student population
at Charles R. Drew University of Medicine and Science is 35% Black and 25% Hispanic. By integrating
student training with the proposed research plan, this grant will help students to acquire considerable
technical skills and the expertise necessary to perform high-quality, basic, and translational biomedical
research.
Terms: <AIDS/HIV><Adipose tissue><Adult-Onset Diabetes Mellitus><Antioncogene Protein p53><Applications Grants><Assay><Automobile Driving><Autoregulation><Award><Binding><Bioassay><Biological Assay><Biomedical Research><Black><Black race><Body Tissues><CUT&RUN><Cancers><Cardiometabolic Disease><Cardiometabolic Disorder><Cardiovascular Diseases><Caring><Cell Body><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Survival><Cell Viability><Cell model><Cells><Cellular Expansion><Cellular Growth><Cellular Proliferation><Cellular Tumor Antigen P53><Cellular model><ChIP Sequencing><ChIP assay><ChIP-seq><ChIPseq><Cleavage Targets and Release Using Nuclease><Cleavage Under Targets and Release Using Nuclease><Clinical><Co-Immunoprecipitations><Coupled><Data><Deposit><Deposition><Development><Diabetes Mellitus><Dietary Fats><Disease><Disease Resistance><Disorder><Dysfunction><Education><Educational aspects><Enrollment><Epidemic><Fats><Fatty Liver><Fatty Tissue><Fatty acid glycerol esters><Foundations><Free Fatty Acids><Functional disorder><Gene Expression><Gene Transcription><Genes><Genetic Transcription><Genotoxic Stress><Gluconeogenesis><Glycogen><Grant><Grant Proposals><HDM2><HIV/AIDS><Health><Health Disparities Research><Health disparities related research><Hepatic><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatocyte><Hispanic><Homeostasis><Human><Humulin R><Hyperglycemia><Impairment><In Vitro><Insulin><Insulin Resistance><Insulin Signaling Pathway><Investigators><Ketosis-Resistant Diabetes Mellitus><Liver><Liver Cells><Liver Steatosis><Liver diseases><Los Angeles><MDM2><MDM2 gene><MDMX protein><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Maturity-Onset Diabetes Mellitus><Mdm-2 protein><Mediating><Medicine><Mentors><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic stress><Mice><Mice Mammals><Minority-Serving Institution><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><NAFLD><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Nonesterified Fatty Acids><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Normal Cell><Novolin R><Nutrient><Obese Mice><Obesity><Oncoprotein MDM2><Oncoprotein p53><Outcome><P53><Pancreas><Pancreatic><Pathway interactions><Phosphoprotein P53><Phosphoprotein pp53><Physiological Homeostasis><Physiopathology><Play><Population><Postbaccalaureate><Prevalence><Protein TP53><Proteins><Publications><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Reading Frames><Regular Insulin><Reporting><Research><Research Personnel><Research Support><Researchers><Risk Factors><Rodent><Rodentia><Rodents Mammals><Role><Science><Scientific Publication><Slow-Onset Diabetes Mellitus><Solid><Stable Diabetes Mellitus><Stress><Students><T2 DM><T2D><T2DM><TP53><TP53 gene><TRP53><Technical Expertise><Thesaurismosis><Tissues><Training><Transcription><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Suppressor Proteins><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Underrepresented Ethnic Minority><Underrepresented Minority><Universities><Up-Regulation><Upregulation><adipose><adiposity><adult onset diabetes><cancer cell><cancer prevention><cardiovascular disorder><cell growth><chromatin immunoprecipitation><chromatin immunoprecipitation-sequencing><cofactor><combat><corpulence><db/db mouse><design><designing><developmental><diabetes><diet-associated obesity><diet-induced obesity><diet-related obesity><dietary lipid><driving><enroll><fat metabolism><glucose RA><glucose biosynthesis><glucose disposal><glucose metabolism><glucose output><glucose production><glucose rate of appearance><graduate student><health disparities science><hepatic body system><hepatic disease><hepatic gluconeogenesis><hepatic organ system><hepatic steatosis><hepatopathy><hepatosteatosis><human model><hyperglycemic><in vivo><insulin resistant><insulin sensitivity><insulin signaling><insulin stimulated glucose disposal><insulin tolerance><ketosis resistant diabetes><knock-down><knockdown><lipid metabolism><liver disorder><malignancy><maturity onset diabetes><mdm-2 oncogene protein><mdm2 protein><member><metabolism disorder><minority institution><model of human><mouse model><murine model><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><non-alcohol fatty liver disease><non-alcoholic fatty liver disease><non-alcoholic liver disease><nonalcoholic fatty liver disease><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ob/ob mouse><overexpress><overexpression><p53 Antigen><p53 Genes><p53 Tumor Suppressor><p53-Binding Protein MDM2><pathophysiology><pathway><postbac><postbacc><prevent><preventing><programs><protein expression><protein function><protein p53><recruit><resistance to disease><resistant disease><resistant to disease><response><restoration><social role><stressor><student training><summer research><technical skills><transcriptome sequencing><transcriptomic sequencing><tumor suppressor><type 2 DM><type II DM><type two diabetes><under-representation of minorities><under-represented minority><undergrad><undergraduate><undergraduate student><underrepresentation of minorities><white adipose tissue><yellow adipose tissue>