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Principal Investigator: Romulo Hurtado
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $577,420
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Abstract
Impaired urinary outflow that causes damage to the urinary tract and kidney is a major cause of kidney disease, which affects 15% of the population and costs $100B annually. For instance, hydronephrosis, a pressure mediated dilation and damage of the renal tissues, is the leading cause of pediatric kidney failure. Major gaps remain in our understanding of the causes that underlie impaired urinary outflow and urinary tract damage. For instance, approximately 50% of all urinary tract dilation occurs in the absence of a physical obstruction, yet the functional abnormalities causing these cases remain obscure. Indeed, the upper urinary tract (UUT) is a continuous muscular organ that contracts to propel waste from the kidney to the bladder. Defects in this peristaltic process, such as vesicoureteral reflux (VUR), or retrograde backward urine flow from the bladder to the kidney, are pathological. VUR affects 2% of children, and can lead to urinary tract infections, hydronephrosis, and chronic reflux nephropathy that leads to end-stage renal disease in 10-25% of cases. Despite the essential physiological role of the UUT, the mechanisms driving UUT peristalsis remained unknown. Our group discovered that HCN ion channels underlie UUT pacemaker activity, that HCN+ pacemakers co-express T-type Ca2+ channels that control contractile rate, and most recently, that the HCN+ pacemakers are evolutionarily conserved and drive peristalsis of the unique multicalyceal UUT exhibited by humans. To date, however, the role of pacemaker defects in functional urinary tract disorders remains elusive. Thus, the overall goal of this proposal is to provide a mechanistic framework of UUT physiology, as a critical step to developing diagnostics and drugs to treat conditions such as VUR and hydronephrosis. To fill the current knowledge gaps, we will use a novel mutant mouse model that exhibits UUTs that lack pacemakers, exhibit normal smooth muscle, and develop VUR and hydronephrosis. We will use this novel mouse model to define the pathophysiology of pacemaker defects that cause urinary dilations. In aim 1 we will define the transcriptional signaling mechanisms that are required for pacemaker formation and functional UUT peristalsis. In aim 2, we will define the transcriptional protein complexomes that assemble to control UUT pacemaker development. Notably, the transcriptional complexomes required for UUT formation remain a major knowledge gap in our understanding of the UUT. Taken together, the proposed studies will provide critical insight into functional peristaltic defects that impede urinary outflow, and results will generate new genetic and protein markers that can serve as putative targets for future diagnostics
and treatments for UUT pathologies, such as VUR and hydronephrosis.
Terms: <0-11 years old><Affect><Assay><Automobile Driving><Basal Transcription Factor><Basal transcription factor genes><Binding><Binding Proteins><Bioassay><Biological Assay><Birth Defects><Bladder><Bladder Urinary System><Causality><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Signaling><Cells><Child><Child Youth><Childhood><Children (0-21)><Chronic><Complex><Congenital Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Contracting Opportunities><Contracts><Coupled><Defect><Development><Diagnostic><Drugs><Dysfunction><ESRD><Electrophysiology><Electrophysiology (science)><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Erinaceidae><Etiology><Excretory function><Exhibits><Functional disorder><Future><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic><Genetic Markers><Genetic Transcription><Goals><Hedgehog (Hh) signal transduction pathway><Hedgehogs><Human><Hydronephrosis><Immune Precipitation><Immunoprecipitation><Impairment><Intracellular Communication and Signaling><Involuntary Muscle><Ion Channel><Ionic Channels><KO mice><Kidney><Kidney Diseases><Kidney Failure><Kidney Insufficiency><Kidney Urinary System><Knock-out Mice><Knockout Mice><Knowledge><Ligand Binding Protein><Ligand Binding Protein Gene><Maps><Measurement><Mediating><Medication><Membrane Channels><Modern Man><Molecular Interaction><Morbidity><Morbidity - disease rate><Muscle><Muscle Tissue><Nephropathy><Neurophysiology / Electrophysiology><Nuclear Matrix><Nuclear Proteins><Nuclear Scaffold><Null Mouse><Obstruction><Operative Procedures><Operative Surgical Procedures><Optics><Organ><Pace Stimulators><Pacemakers><Pathologic><Pathologic Processes><Pathological Processes><Pathology><Pathway interactions><Peristalsis><Pharmaceutical Preparations><Physiologic><Physiological><Physiology><Physiopathology><Population><Process><Progenitor Cells><Protein Binding><Proteins><RNA Expression><Reflux><Regulation><Renal Disease><Renal Failure><Renal Insufficiency><Renal Tissue><Research><Role><Scaffolding Protein><Signal Transduction><Signal Transduction Systems><Signaling><Smooth Muscle><Specific qualifier value><Specified><Surgical><Surgical Interventions><Surgical Procedure><Techniques><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Urinary Tract Diseases><Urinary Tract Physiology><Urinary tract><Urinary tract infection><Urinary tract infectious disease><Urine><Urologic Diseases><Urologic Disorder><Urological Diseases><Urological Disorders><Vesico-Ureteral Reflux><Vesicoureteral Reflux><biological signal transduction><bound protein><cardiac pacemaker cell><causation><cellular differentiation><cofactor><conditional knock-out><conditional knockout><cost><damage to kidney><developmental><disease causation><driving><drug/agent><electrophysiological><excretion><gene biomarker><gene expression biomarker><gene marker><gene signature biomarker><genetic biomarker><hedgehog signaling><hedgehog signaling pathway><hh signaling pathway><insight><kidney damage><kidney disorder><kids><mouse model><murine model><muscular><mutant mouse model><nodal myocyte><novel><optical><organ development><organ growth><pacemaker cell><patch clamp><pathophysiology><pathway><pediatric><pressure><protein biomarkers><protein markers><real-time images><realtime image><renal><renal damage><renal disorder><smoothened signaling pathway><social role><stem cells><surgery><transcription factor><transcriptomics><urinary><urinary bladder><urinary infection><urinary tract disorder><wasting><youngster>