Document text
Principal Investigator: Anna Greka
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $390,369
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
SUMMARY
Chronic kidney diseases affect more than 700 million people worldwide, and are a frequent cause
of kidney failure and death. A key event leading to kidney failure is filter damage, caused by the
loss of podocytes. This is a cause of a kidney disease known as Focal segmental
Glomerulosclerosis (FSGS). Despite the growing prevalence of kidney diseases, there are
currently no FDA approved therapies to prevent the loss of podocytes. The goal of this grant
application is to gain a deep understanding of the molecular mechanisms involved in podocyte
injury related to the BRAF signaling pathway, so that it may be targeted for therapeutic benefit.
We started with a rare genetic kidney disease caused by mutations in an enzyme called PDSS2.
Interestingly, we found that the loss of function of this enzyme causes podocytes to die, resulting
in FSGS. We subsequently found that a key molecule in preventing podocyte death is BRAF and
a small molecule that activates BRAF, called GDC-0879, can protect podocytes from cell death.
In fact, GDC-0879 was able to protect podocytes from several injuries including toxic lipids and
other stress-causing molecules. Most excitingly, we now have evidence that GDC-0879 protects
mice from podocyte injury and the resulting kidney filter damage (called proteinuria). Here, we will
explore the precise molecular mechanisms involved in BRAF-related podocyte injury, and the
potential for GDC-0879 to become a treatment for FSGS.
Successful completion of this work may provide a new, much needed treatment for FSGS and
chronic kidney diseases, and one that may be easily brought to the clinic, since GDC-0879 is
already an FDA approved drug for other indications.
Terms: <Address><Affect><Angiotensin AT1 Receptor><Angiotensin II Type 1 Receptor><Antioxidants><Applications Grants><B-raf-1><BRAF><BRAF gene><Body Tissues><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cell membrane><Cells><Cessation of life><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinic><Co-Q10><CoQ 10><CoQ10><Coenzyme Q10><Cytoplasmic Membrane><Data><Death><Development><Drugs><ER stress><Enzyme Gene><Enzymes><Event><Extracellular Signal-Regulated Kinase Gene><FDA approved><FSGS><Focal and Segmental Glomerulosclerosis><Focal segmental glomerular sclerosis><Funding><Gene Expression><Generations><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><Grant><Grant Proposals><Human><In Vitro><Injury><Intracellular Communication and Signaling><Ion Channel><Ionic Channels><Kidney><Kidney Diseases><Kidney Failure><Kidney Insufficiency><Kidney Urinary System><Lipids><MAP Kinase Gene><MAPK><Mediating><Medication><Membrane Channels><Mice><Mice Mammals><Mitochondria><Mitogen-Activated Protein Kinase Gene><Modeling><Modern Man><Molecular><Murine><Mus><Mutation><Nephropathy><Nephrotic Syndrome><Pathway interactions><Patients><Persons><Pharmaceutical Preparations><Plasma Membrane><Prevalence><Proteinuria><Publishing><RAFB1><Receptor Signaling><Receptor, Angiotensin, Type 1><Renal Disease><Renal Failure><Renal Insufficiency><Retinoic Acid Receptor><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Testing><Therapeutic><Tissues><Up-Regulation><Upregulation><Visceral Epithelial Cell><Work><angiotensin II type I receptor><autosome><biological signal transduction><chronic kidney disease><developmental><drug/agent><endoplasmic reticulum stress><fat metabolism><genome mutation><glomerular visceral epithelial cell><in vivo><injuries><innovate><innovation><innovative><insight><kidney disorder><lipid metabolism><loss of function><metabolism measurement><metabolomics><metabonomics><mitochondrial><necrocytosis><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><pathway><plasmalemma><podocyte><postmitotic><prevent><preventing><rare allele><rare mutation><rare variant><renal><renal disorder><rho G-Proteins><rho GTP-Binding Proteins><rho GTPases><rho Protein P21><rho Small GTP-Binding Proteins><small molecule><stressor><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptomics><ubidecarenone><ubiquinone 50><ubiquinone Q10><v-raf Murine Sarcoma Viral Oncogene Homolog B1>