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Principal Investigator: Laith Al-Rabadi
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2024
Award: $174,960
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Abstract
Primary membranous nephropathy (MN) is a major cause of nephrotic syndrome and kidney diseases.
This autoimmune condition is characterized by the accumulation of immune complexes along the glomerular
basement membrane (GBM). What triggers autoantibody production and its contribution to organ damage in MN
remains incompletely understood. As such, further understanding of these pathological events could enable
timely diagnosis and an overall improvement of treatment outcome in MN. Our previous interdisciplinary
proteomic approach identified the serine protease HTRA1 as a novel autoantigen in MN. In this “Mentored
Clinical Scientist Research Career Development (K23) Award”, mechanistic studies will be implemented to
identify the precise pathogenic HTRA1 epitopes targeted by autoantibodies and their impact on HTRA1 protein
function (Aim 1). Furthermore, contributions of HTRA1 autoantibodies as well as HTRA1 antigen accumulation
to disease development will be investigated in newly developed animal models of MN (Aim 2).
This five-year proposal aims to support the transition of the candidate from a junior physician scientist to
an independent investigator in nephrology under the mentorship of leading experts in immunology, nephrology,
and other relevant fields (Drs. Haecker, Beck, and Hageman). Building upon the candidate’s strong clinical
experience (running the glomerular disease clinic at the University of Utah and utilizing biospecimens from the
national MN clinical research network of CureGN, ARUP, and Arkana laboratories) and prior research exposure
in glomerular disease, various intensive training modules will be designed to refine his scientific knowledge.
Career development training will also be implemented to prepare the candidate with the necessary
communication and leadership skills to become an independent investigator. Lastly, access to ample resources
to support the aforementioned scientific studies and educational programs will ensure a timely successful
execution of this proposal, allowing the candidate to begin his career path of scientific independence.
Terms: <Albuminuria><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody titer measurement><Antigen Targeting><Antigen-Antibody Complex><Antigenic Determinants><Antigens><Assay><Autoantibodies><Autoantigens><Autoimmune Diseases><Autoimmune Mechanism><Autoimmune Process><Autoimmune Responses><Autologous Antigens><Automobile Driving><Autoregulation><Award><Basement membrane><Binding><Binding Determinants><Bioassay><Biological Assay><Blood><Blood Reticuloendothelial System><Blood Serum><Body Tissues><Brain><Brain Nervous System><Bruch Membrane><Bruch's basal membrane structure><Bruch's membrane><Bruchs membrane><Career Choice><Career Path><Cell-Extracellular Matrix><ChIP assay><Circulation><Clinic><Clinical><Clinical Research><Clinical Study><Communication><Data><Deposit><Deposition><Development><Diagnosis><Disease><Disorder><Domestic Rabbit><ECM><ESRD><Education><Educational aspects><Electron Microscopy><Encephalon><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Endothelial Cells><Ensure><Epitopes><Esteroproteases><Event><Extracellular Matrix><Extracellular Matrix Proteins><Extramembranous Glomerulopathy><Eye><Eye diseases><Eyeball><Filtration><Filtration Fractionation><Foundations><Generations><Glomerular disease><Goals><Heteroantibodies><Heterogenetic Antibodies><Heterologous Antibodies><Heterophil Antibodies><Heterophile Antibodies><Heterotypic Antibodies><Histologic><Histologically><Homeostasis><Human><Immune Complex><Immune response><Immunization><Immunize><Immunofluorescence><Immunofluorescence Immunologic><Immunological response><Immunology><In Situ><In Vitro><Injury><Investigators><Junior Physician><KO mice><Kidney><Kidney Diseases><Kidney Glomerulus><Kidney Urinary System><Knock-out Mice><Knockout Mice><Knowledge><Laboratories><Lamina Basalis Choroideae><Leadership><Malpighian Tuft><Mediating><Membranous Glomerulonephritis><Membranous Glomerulonephropathy><Membranous Glomerulopathy><Membranous Nephropathy><Mentors><Mentorship><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Nephrology><Nephropathy><Nephrotic Syndrome><Null Mouse><Organ><Oryctolagus cuniculus><Pathogenesis><Pathogenicity><Pathologic><Pathology><Patients><Peptidases><Peptide Hydrolases><Peptides><Physiological Homeostasis><Pre-Clinical Model><Preclinical Models><Production><Protease Domain><Protease Gene><Proteases><Protein Fragment><Protein Secretion><Proteinases><Proteins><Proteinuria><Proteolytic Domain><Proteolytic Enzymes><Proteomics><Rabbits><Rabbits Mammals><Renal Disease><Renal Glomerular Diseases and Syndromes><Renal glomerular disease><Renal glomerular disease or syndrome><Renal glomerular disorder><Renal glomerular syndrome><Research><Research Personnel><Research Resources><Researchers><Resources><Rodent><Rodentia><Rodents Mammals><Running><Scientist><Self-Antigens><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><Serum><Site><Structure><Testing><Therapeutic><Time><Tissues><Training><Training Activity><Transgenic Model><Treatment outcome><Universities><Utah><Visceral Epithelial Cell><Xenoantibodies><Xenogeneic Antibodies><Xenogenic Antibodies><antibody titering><autoimmune antibody><autoimmune condition><autoimmune disorder><autoimmunity disease><autoreactive antibody><career aspiration><career development><career interest><career pathway><career track><chromatin immunoprecipitation><clinical development><clinical relevance><clinically relevant><cohort><design><designing><developmental><driving><experience><eye disorder><glomerular basement membrane><glomerular filtration><glomerular visceral epithelial cell><host response><immune system response><immunogen><immunoresponse><improved><in vivo><injuries><insight><kidney disorder><kidney glomeruli><model of animal><novel><ocular disease><ocular disorder><ophthalmopathy><overexpress><overexpression><podocyte><programs><protein function><protein protein interaction><renal><renal disorder><renal glomerulus><response><self reactive antibody><skills><training module><transgenic trait><trypsin-like serine protease>