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Principal Investigator: Alexander H Flannery
Organization: UNIVERSITY OF KENTUCKY
Fiscal Year: 2024
Award: $99,759
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY/ABSTRACT
This proposal includes a five-year research career development program to study classical and alternative
renin-angiotensin system (RAS) dysregulation in sepsis-associated acute kidney injury (SA-AKI). The
candidate is currently an Assistant Professor at the University of Kentucky College of Pharmacy. The proposal
builds on the candidate’s strong background in clinical research on AKI and integrates mentorship from
established investigators in sepsis, AKI, RAS therapeutics, and murine models of SA-AKI. The proposed
career development activities will equip the candidate with the skills necessary to become established as an
independent clinical and translational scientist conducting patient-oriented research on SA-AKI. Over 4 million
patients are hospitalized annually with AKI, and sepsis is estimated to contribute to 26-50% of all cases.
Current therapy is limited to supportive care and kidney replacement therapy. Recent evidence suggests
sepsis causes a disruption in angiotensin converting enzyme (ACE) and ACE2 that could severely dysregulate
the RAS. This disruption may ultimately result in local excess of the proinflammatory, classical RAS and
deficiencies in the counter-regulatory, anti-inflammatory alternative RAS (Alt-RAS). An intra-renal RAS,
operating independently from the circulatory RAS, may drive pathophysiology and urinary RAS biomarkers
have been proposed as surrogate markers of intra-renal RAS activation. Using a bedside-to-bench approach,
our overall objective is to quantify the classical and Alt-RAS disturbances present at the circulatory and tissue
level in SA-AKI, and evaluate the relationship between the extent of this disturbance and major adverse kidney
events. Our central hypothesis is that a deficiency of the regenerative RAS, or Alt-RAS, exists relative to the
classical RAS in SA-AKI at the circulatory and tissue level, and that the degree of this imbalance differentially
associates with outcomes in patients with SA-AKI. We propose three specific aims to accomplish this: (1) To
determine the relationship between RAS dysregulation, kidney biomarkers of tubular injury and function, and
major adverse kidney events within 30 days (MAKE-30) in SA-AKI, (2) To assess the relationship between
urinary biomarkers of intra-renal RAS activation and MAKE outcomes out to one year in critically ill patients
with SA-AKI and heterogenous AKI, and (3) To test the hypothesis that the kidney RAS peptide metabolome
and receptor expression profile shift to a regenerative or Alt-RAS deficiency in a murine model of SA-AKI, and
that the degree of Alt-RAS deficiency (relative to classical RAS) corresponds to the degree of kidney injury and
intra-renal RAS activation. Career development activities that align with this research include: training in
application of laboratory assays including mass spectrometry, advancement of statistical analysis skills with
longitudinal data and introductory machine learning, and learning pre-clinical models of SA-AKI. This proposal
supports the mission of NIDDK by furthering the understanding of SA- AKI, a leading cause of AKI and kidney
complications impacting the public’s health and quality of life.
Terms: <ACE2><Acute><Acute Renal Failure with Renal Papillary Necrosis><AngII><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin II><Angiotensin-Forming Enzyme><Angiotensinogen><Angiotensinogenase><Angiotensins><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Assay><Bioassay><Biological Assay><Biological Markers><Body Tissues><CD143 Antigens><Carboxycathepsin><Causality><Chronic><Chronic Disease><Chronic Illness><Classification><Clinical><Clinical Research><Clinical Study><Critical Illness><Critically Ill><Data><Death Rate><Development><Dipeptidyl Peptidase A><Dysfunction><ESRD><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Etiology><Event><Evolution><Frequencies><Functional disorder><Future><Health><Hospital Admission><Hospitalization><Hypertensinogen><Infection><Inflammatory><Injury><Injury to Kidney><Investigators><Kentucky><Kidney><Kidney Replacement Therapy><Kidney Urinary System><Kininase A><Kininase II><Laboratories><Learning><Machine Learning><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measurement><Measures><Mentorship><Mice><Mice Mammals><Mission><Modeling><Murine><Mus><NIDDK><National Institute of Diabetes and Digestive and Kidney Diseases><Outcome><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peptides><Peptidyl-Dipeptidase A><Pharmacies><Pharmacy facility><Physiopathology><Pre-Clinical Model><Preclinical Models><Proangiotensin><Program Development><Prospective cohort><Proteins><Public Health><QOL><Quality of life><Receptor Protein><Recovery><Renal Replacement Therapy><Renin><Renin-Angiotensin System><Renin-Substrate><Research><Research Personnel><Researchers><Risk><Risk Marker><Role><Sepsis><Septic Shock><Statistical Data Analyses><Statistical Data Analysis><Statistical Data Interpretation><Supportive Therapy><Supportive care><Surrogate Markers><Systematics><Testing><Therapeutic><Tissues><Training><Translational Research><Translational Science><Tubular><Tubular formation><Universities><Up-Regulation><Upregulation><Urine><acute kidney injury><angiotensin converting enzyme 2><angiotensin converting enzyme II><bench bed side><bench bedside><bench to bed side><bench to bedside><bench to clinic><bench to clinical practice><bio-markers><biobank><biologic marker><biomarker><biorepository><blood infection><bloodstream infection><career development><causation><chronic disorder><clinical care><clinical translation><clinically translatable><cohort><college><collegiate><complex biological systems><damage to kidney><developmental><disease causation><improved><injuries><kidney damage><kidney injury><machine based learning><metabolism measurement><metabolome><metabolomics><metabonome><metabonomics><molecular biomarker><molecular marker><mortality rate><mortality ratio><mouse model><murine model><pathophysiology><patient oriented outcomes><patient oriented research><patient oriented study><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><professor><receptor><receptor expression><regenerative><renal><renal damage><renal injury><response><risk predictor><risk predictors><skills><social role><statistical analysis><surrogate bio-markers><surrogate biomarkers><translation research><translation strategy><translational approach><translational investigation><translational investigator><translational model><translational researcher><translational scientist><translational strategy><urinary>