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Principal Investigator: PETER Kent JACKSON
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $506,154
Funding agency: National Institute of General Medical Sciences
This project focuses on understanding a fundamental cellular mechanism underlying a range of important
physiological signaling in humans including the control of feeding and obesity. The mechanism uses an ancient
cellular signaling organelle, the primary cilium, to control responses to satiety signals generated following feeding.
Bardet-Biedl syndrome (BBS) is a rare human syndrome called a ciliopathy because of mutations in genes encoding
components of the primary cilium. Patients with BBS have inherited mutations in genes linked to a complex called
the BBSome, discovered in our laboratory, that fail to present receptors critical to limit feeding after a meal. Our
work has found that cilia also control adipogenesis via the de novo generation of new fat cells and the secretion of
insulin and glucagon in pancreatic islet cells. We have focused on mechanisms of ciliary signaling and trafficking,
enabled by the use of affinity purification/mass spectrometry to identify new components of the ciliary machinery.
These studies have been initiated by using the ciliopathy disease genes as bait proteins to find new components
and cell biological pathways linked to ciliary traffic and signaling. A number of these newly discovered components
are themselves mutated in human pedigrees linked to obesity. In particular, a ciliary structure called the distal
appendage serves as a critical gate for entry of ciliary receptors. We find that mutations in components of the distal
appendage are linked to monogenic obesity syndromes. As monogenic obesity syndromes are rare, the lab has
shifted to systematically surveying public data for over 750,000 patients in Genome Wide Association Studies
(GWAS) for genes found to be altered in patients with high Body Mass Index (BMI) (a key measure of obesity) and
diabetes. We have discovered 100s if not 1000s of candidates for a substantially broader list of candidates for
obesity drivers linked to cilia in nonconsanguineous populations. In Aim 1 of this proposal, we will further explore
the mechanisms by which the distal appendage is assembled and how that organizes trafficking into the cilium. In
Aim 2, we will examine how the distal appendage traffics receptors and generates signals in the cell. In Aim 3, we
will explore a new factor of the distal appendage, called CCDC92, which potentially controls signaling via proteolytic
destruction of ciliary signaling regulators. In each Aim, we will use genetic lesions derived from patients with high
BMI which we find have screened for defects in ciliary trafficking or signaling. Our goals are to continue to explain
obesity lesions to allow accurate assessment of a patient’s genetic obesity drivers, to identify additional druggable
targets for obesity and diabetes therapeutics, and to communicate these findings to the public to help predict dietary
susceptibilities based on molecular genetic profiles. By identifying signaling pathways defective in obesity and
diabetes, we can identify targets to protect or restore these tissues and molecular profiles of patients to facilitate
patient selection for treatments to improve obesity and metabolic disease.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><26 S proteasome complex><26S ATP-Dependent Protease><26S ATP-Dependent Proteasome><26S Proteasome Complex><26S Proteosome><26S protease><26S proteasome><Abscission><Adipocytes><Adipose Cell><Affect><Affinity Chromatography><Antidiabetic Hormone><Automobile Driving><B9 endocrine pancreas><Bardet Biedel syndrome><Bardet-Biedl Syndrome><Binding><Binding Proteins><Biological><Body Tissues><CRISPR><CRISPR/Cas system><Cancers><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cells><Cellular biology><Centrioles><Centrosome><Cilia><Clinical Research><Clinical Study><Clustered Regularly Interspaced Short Palindromic Repeats><Communication><Complex><Coupling><Data><Defect><Diabetes Mellitus><Diagnosis><Disease><Disorder><Distal><Docking><Drosophila Homolog of Frequenin><Embryo><Embryonic><Endocrine><Endocrine Pancreas><Endosomes><Excision><Extirpation><FREQ gene><FREQ protein><Fat Cells><Feedback><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G Protein-Coupled Receptor Signaling><G-Protein-Coupled Receptors><GPCR><GPCR Signaling><GWA study><GWAS><Gene Transcription><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Glucagon><Glukagon><Goals><HG-Factor><Health><Hereditary><Hormone Receptor><Hormone secretion><Human><Human Genetics><Hyperglycemic-Glycogenolytic Factor><Inherited><Interacinar Cell Pancreatic Polypeptide><Intracellular Communication and Signaling><Islands of Langerhans><Islet Cell><Islets of Langerhans><KO mice><Kinases><Knock-out Mice><Knockout Mice><Laboratories><Lesion><Ligand Binding Protein><Ligand Binding Protein Gene><Ligands><Link><Lipocytes><Macropain><Macroxyproteinase><Malignant Neoplasms><Malignant Tumor><Manuscripts><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mature Lipocyte><Mature fat cell><Measures><Mediating><Membrane><Metabolic Diseases><Metabolic Disorder><Metabolic Protein Degradation><Micro-tubule><Microtubules><Modeling><Modern Man><Molecular><Molecular Fingerprinting><Molecular Genetics><Molecular Interaction><Molecular Profiling><Mothers><Multicatalytic Proteinase><Mutate><Mutation><NCS1><Nesidioblasts><Neuronal Calcium Sensor 1><Null Mouse><Obesity><Organelles><Pancreatic Islets><Pancreatic Polypeptide><Pars endocrina pancreatis><Pathogenesis><Pathology><Pathway interactions><Patient Selection><Patients><Pedigree><Phenotype><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiological><Play><Population><Predisposition><Preparation><Process><Prosome><Proteasome><Proteasome Endopeptidase Complex><Protein Binding><Protein Turnover><Proteins><Proteomics><Proteosome><RNA Expression><Receptor Protein><Receptosomes><Recycling><Regulation><Regulatory Protein Degradation><Removal><Role><Satiation><Selection for Treatments><Sensory><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Situs Inversus><Structure><Surgical Removal><Survey Instrument><Surveys><Susceptibility><Syndrome><TPKI kinase><Technology><Testing><Therapeutic><Thesaurismosis><Tissues><Transcription><Transphosphorylases><Vesicle><Work><adipogenesis><adiposity><affinity purification><appendage><base><bases><biologic><biological signal transduction><bound protein><cell biology><cell culture><cell cultures><ciliopathy><corpulence><developmental disease><developmental disorder><diabetes><dietary><driving><druggable target><extracellular><feeding><genetic pedigree><genome mutation><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><heterotaxia syndrome><heterotaxy><high BMI><high body mass index><hormonal secretion><improved><insulin secretion><inversion of viscera><islet progenitor><laterality sequence><lipid biosynthesis><lipogenesis><malignancy><membrane structure><metabolism disorder><molecular profile><molecular signature><multicatalytic endopeptidase complex><myristoylation><neoplasm/cancer><novel><obesity genetics><pathway><patient profile><pedigree structure><phospho-proteomics><phosphoproteomics><preparations><profiles in patients><protein degradation><protein function><rare condition><rare syndrome><receptor><recruit><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><resection><response><satiety><scaffold><scaffolding><screening><screenings><selection of treatment><situs abnormality><situs inversus viscerum><social role><tau kinases><tau protein kinase I><tau-protein kinase><tau-tubulin kinase><therapy selection><tissue regeneration><tissue regrowth><tissue renewal><tissue specific regeneration><trafficking><transposition of viscera><treatment selection><visceral heterotaxy><visceral transposition><whole genome association analysis><whole genome association studies><whole genome association study><τ-protein kinase><τ-tubulin kinase>