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Principal Investigator: Meenakshi Arora
Organization: UNIVERSITY OF ALABAMA IN TUSCALOOSA
Fiscal Year: 2024
Award: $310,226
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary
The etiology of acute kidney injury (AKI), a common disease, can be multifactorial and currently has no FDA-
approved drugs for its prevention or treatment. Emerging evidence from laboratory and clinical studies
suggests the pathogenesis involves reactive oxygen species (ROS) generation, activation of inflammatory and
apoptotic pathways; therefore, regulating these pathways offer protection. Given the antioxidant, anti-
inflammatory and antiapoptotic effects of urolithin A (UA), a gut microbial metabolite of ellagic acid, the aim of
this project is to explore the therapeutic potential of UA in AKI. However, UA's therapeutic potential is
constrained by poor bioavailability. The work enabled by previous findings, in which oral delivery of UA was
achieved by biodegradable nanoparticles that utilize a surface conjugated ligand targeting the gut-expressed
transferrin receptor. Nanoparticle encapsulation of UA led to a ~7 and ~6-fold enhancement in oral
bioavailability compared to native UA in healthy rodents and dogs respectively. Treatment with nanoparticle UA
also significantly attenuated the histopathological hallmarks of cisplatin-induced AKI and reduced mortality by
63% in the mouse model. This project will further develop UA as a potential therapeutic for treating AKI,
considering the fact that cisplatin is utilized only in individuals with cancer who are administered repeated low
doses in the clinic. The overall goal will be accomplished by pursuing the following independent specific aims.
Aim 1, will define the extent to which structural elements of the delivery system and the pathophysiology can
influence UA bioavailability. Aim 2, will assess the protective benefits of the most bioavailable form of UA in
dose and age dependent cisplatin-induced AKI, as well as desired and undesired effects of UA combined with
cisplatin in cancer setting. Aim 3 will establish efficacy of UA against cisplatin-induced AKI in healthy dogs
(non-cancerous), who will be re-homed as pets at the end of the study. At the end of the proposed studies, we
will understand and fully be able to describe how effective delivery influences the pharmacology of UA, with
regards to both desired and undesired effects in mice and dog models. The knowledge gained will be valuable
in developing UA as not only an oral therapeutic for AKI and for other vascular and neuroinflammatory
diseases in which plain UA has shown some benefit, but also as an adjuvant in combination therapies for
cancer treatment, where immediate clinical testing in dogs (cancer patients) can be carried out.
Terms: <Abbreviations><Active Oxygen><Acute Renal Failure with Renal Papillary Necrosis><Address><Adjuvant><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antioxidants><Apoptotic><Attenuated><Benchmarking><Benzoaric Acid><Best Practice Analysis><Bioavailability><Biological Availability><Blood Vessels><Body Tissues><CD71><CDDP><Cancer Patient><Cancer Treatment><Cancers><Canine Species><Canis familiaris><Carbon><Carcinoma><Causality><Characteristics><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clinic><Clinical><Clinical Evaluation><Clinical Research><Clinical Study><Clinical Testing><Core Particle><Cysplatyna><Cytotoxic agent><Cytotoxic drug><Data><Development><Dichlorodiammineplatinum><Disease><Disorder><Dogs><Dogs Mammals><Dose><Drug Kinetics><Drugs><Dysfunction><Elements><Ellagic Acid><Encapsulated><Epithelial cancer><Etiology><Excretory function><FDA approved><Formulation><Functional disorder><Generations><Goals><Human><Impairment><Individual><Inflammatory><Kidney Diseases><Knowledge><Laboratory Study><Length><Length of Stay><Ligands><Literature><Malignant Cell><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Mediating><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Mice><Mice Mammals><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Murine><Mus><Neoplasm Metastasis><Nephropathy><Nucleosome Core><Nucleosome Core Particle><Number of Days in Hospital><Oncology><Oncology Cancer><Oral><Outcome><Ovary Cancer><Oxygen Radicals><Pathogenesis><Pathway interactions><Patients><Performance><Periodicals><Peritoneal><Peyrone's Chloride><Peyrone's Salt><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology><Physiologic Availability><Physiopathology><Platinum Diamminodichloride><Polyesters><Prevention><Pro-Oxidants><Public Health><Reactive Oxygen Species><Receptor Protein><Regimen><Renal Disease><Renal function><Research><Resistance><Rodent><Rodentia><Rodents Mammals><Safety><Secondary Neoplasm><Secondary Tumor><Siderophilin><Speed><Surface><Syndrome><System><TFR gene><TFR protein><TFR1><TFRC><TFRC gene><TRFR><Testing><Therapeutic><Tissues><Transferrin><Transferrin Receptor><Transferrin Receptor 1><Tubular><Tubular formation><Unresectable><Work><acute kidney injury><age associated><age correlated><age dependent><age linked><age related><age specific><anti-cancer therapy><attenuate><attenuates><benchmark><cancer cell><cancer metastasis><cancer therapy><cancer-directed therapy><canine><canine animal model><canine model><causation><chemotherapy><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><clinical test><clinical translation><clinically translatable><combination cancer therapy><comparative><cost><density><design><designing><developmental><disease causation><dog model><domestic dog><dosage><drug/agent><effective therapy><effective treatment><epithelial carcinoma><excretion><glomerular filtration><hospital days><hospital length of stay><hospital stay><improved><intestinal barrier><intestinal mucosal barrier><kidney disorder><kidney function><malignancy><microbial><mortality><mouse model><multi-modal cancer therapy><multi-modal neoplasm therapy><multimodality cancer therapy><multimodality neoplasm therapy><murine model><nano particle><nano polymer><nano-sized particle><nanoparticle><nanoparticle therapy><nanopolymer><nanosized particle><neoplasm/cancer><neural inflammation><neuroinflammation><neuroinflammatory><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ovarian cancer><particle><pathophysiology><pathway><periodic><periodical><pet animal><pets><receptor><renal disorder><research clinical testing><resistant><side effect><success><therapeutic nanoparticles><therapeutic outcome><therapeutic target><therapy outcome><tumor><tumor cell metastasis><uptake><urinary><vascular>