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Principal Investigator: Rahaf Shishani
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2024
Award: $41,972
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
Dysregulation of pancreatic islet function is a hallmark of type 2 diabetes mellitus (T2DM) progression. Thus,
understanding the exact mechanisms by which islet function can be preserved and regulated is crucial. It is
increasingly evident that α-cells play an important role in the potentiation of glucose-stimulated insulin secretion
(GSIS), thereby expanding their function beyond that of the traditional counterregulatory role. However, the
regulation of intra-islet communication and its role in maintaining normal islet function remains incompletely
defined. Endogenous potentiators of β-cell function include glucagon and glucagon-like peptide-1 (GLP-1). While
GLP-1 and glucagon both potentiate GSIS by binding to the GLP-1 receptor (GLP-1R) on the β-cell, GLP-1 is
300-fold more potent at promoting GSIS than glucagon. Canonically, glucagon is produced by the α-cell, and
GLP-1 is produced by the enteroendocrine L-cells in the gut. However, a growing body of literature reports that
under pathophysiological conditions, α-cells can produce and secrete active GLP-1. Our lab has identified the
signaling protein 14-3-3-ζ as a key regulator of α-cell endocrine profile. Specifically, we have found that β-cell
14-3-3-ζ ablation and inhibition increases GSIS and activates α-cell active GLP-1 production and secretion in
mouse and human islets in vitro. How β-cell 14-3-3-ζ expression is regulated and the role of the α-cell in the
impact of β-cell 14-3-3-ζ on islet function is unknown. Therefore, the driving hypothesis of this project is that
β-cell 14-3-3-ζ is a crucial regulator of α-cell to β-cell crosstalk. I will pursue our hypothesis in the following
aims: Aim 1 will define a new pathway regulating β-cell14-3-3-ζ expression. Specifically, our lab has found that
enhanced β-cell GLP-1R signaling decreases 14-3-3-ζ expression in the β-cell. I will study β-cells and mouse
and human islets to define the key signaling nodes by which β-cell GLP-1R signaling decreases 14-3-3-ζ
expression. Aim 2 will determine the efficacy of targeting 14-3-3-ζ in the β-cell to improve islet function in high
fat diet-fed mice. Aim 3 will determine the effect of β-cell 14-3-3-ζ ablation on bidirectional islet cell crosstalk.
Through these carefully designed experiments, I aim to shed light on a new crosstalk mechanism between α-
cells and β-cells, potentially opening new avenues for understanding and treating T2DM. The training plan will
be facilitated by the mentorship of my sponsor, mentorship team and the exceptional facilities and graduate
student support at UC Davis. This proposal describes an integrative and comprehensive training plan to support
my scientific and professional development and propel me toward my long-term goal of becoming an
independent researcher focused on the molecular underpinnings of metabolic disease.
Terms: <3'5'-cyclic ester of AMP><3,5 cyclic AMP synthetase><ATP-protein phosphotransferase><Ablation><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adenyl Cyclase><Adenylate Cyclase><Adenylyl Cyclase><Adult-Onset Diabetes Mellitus><Advisory Committees><Agonist><Alpha Cell><Antidiabetic Hormone><Automobile Driving><Beta Cell><Binding><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chemosensitization><Chemosensitization/Potentiation><Committee Members><Communication><Cyclic AMP><Cyclicity><D-Glucose><Data><Development><Dextrose><Disease><Disorder><Down-Regulation><Endocrine><Epidemic><Experimental Designs><Fat-Restricted Diet><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GLP-1><GLP-1 receptor><GLP-I receptor><GPCR><Gases><Glucagon><Glucagon Cell><Glucagon Secreting Cell><Glucose><Glukagon><Goals><HG-Factor><Health><High Fat Diet><Human><Humulin R><Hyperglycemic-Glycogenolytic Factor><In Vitro><Insulin><Insulin Cell><Insulin Secreting Cell><Intracellular Communication and Signaling><Investigators><Islet Cell><KO mice><Ketosis-Resistant Diabetes Mellitus><Kinase Family Gene><Knock-out><Knock-out Mice><Knockout><Knockout Mice><L Cells><Lab Findings><Laboratory Finding><Literature><Low-Fat Diet><Maturity-Onset Diabetes Mellitus><Mediator><Mentorship><Messenger RNA><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Modern Man><Molecular><Molecular Interaction><Murine><Mus><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Null Mouse><Pathway interactions><Periodicity><Play><Potentiation><Prevalence><Production><Protein Kinase><Protein Secretion><Proteins><Proteomics><Reagent><Receptor Signaling><Regular Insulin><Regulation><Reporting><Research Personnel><Research Proposals><Researchers><Rhythmicity><Role><Saline><Saline Solution><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Subcellular Process><T2 DM><T2D><T2DM><Task Forces><Testing><Thesaurismosis><Training><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><adenosine 3'5' monophosphate><adult onset diabetes><advisory team><alpha-cell><antagonism><antagonist><biological signal transduction><blood glucose regulation><cAMP><determine efficacy><developmental><driving><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><global health><glucagon-like peptide 1><glucagon-like peptide-1 receptor><glucose control><glucose homeostasis><glucose regulation><glycogen synthase a kinase><graduate student><hydroxyalkyl protein kinase><improved><insight><insulin secretion><islet><ketosis resistant diabetes><mRNA><maturity onset diabetes><metabolism disorder><novel><pancreatic islet function><pathway><phosphorylase b kinase kinase><preservation><pro-glucagon><proglucagon><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><type 2 DM><type II DM><type two diabetes><α-cell><β-cell><β-cells><βCell>