Multifaceted Approaches to Prevent Ammonium Urate Crystallization in Bottlenose Dolphin Renal Stones (20-000000235)
Abstract
Kidney stones have emerged as a significant health risk for Navy dolphins. In this proposal, we utilize multifaceted approaches to develop therapies to prevent the formation of ammonium urate (NH4U) crystals in bottlenose dolphin renal stones. A team of researchers with synergistic expertise from the University of Houston (UH), National Marine Mammal Foundation (NMMF), Epitracker (ET), and the University of Texas Southwestern (UTSW) Medical School will use a combination of state-of-the-art characterization techniques (spanning macroscopic to microscopic levels) in crystal engineering and data analytics of dolphin urine to identify (macro)molecules that suppress nucleation and/or growth of NH4U crystals. This project will focus on three integrated areas of research: (i) elucidating lead candidates as inhibitors of dolphin stones using a combination of in vitro screening assays, metabolomics, and data analytics of dolphin urine samples; (ii) investigating detailed mechanisms of inhibitor-crystal interactions to establish structure-property relationships that are critical for predicting effective inhibitors; and (iii) identifying bioavailable molecules that function as crystal growth inhibitors (or promoters) using dolphin urine screening assays with the goal of selecting viable treatments for future in vivo (e.g. animal) studies. The overarching goal of this project is to improve Navy dolphin health and establish therapeutics to prevent ammonium urate stone formation in both dolphins and humans.The specific aims of this project are subdivided into four primary research tasks. Task 1 involves the identification of inhibitors where a library of molecules refined through iterative data mining and in vitro crystal growth assays will be assessed for their potential efficacy and potency as inhibitors of ammonium urate formation. The most promising inhibitors will be examined by more systematic studies in Task 2, which will focus on elucidating the mechanisms of crystal growth inhibition and promotion. These thrusts will address two fundamental aspects of NH4U crystallization: native conditions that promote crystal formation in vivo and the use of inhibitors as potential therapeutics to prevent crystal formation. These studies will leverage state-of-the-art techniques capable of resolving molecular level details of layered growth on crystal surfaces to develop general heuristics that aid the treatment of dolphin kidney stones. Task 3 will transition to studies in dolphin urine where outcomes of the previous tasks will be leveraged in an effort to understand the effects of inhibitors in native environments of dolphin kidney stones where cooperative interactions of inhibitors in complex media are not well understood. In Task 4 we will further optimize crystal growth inhibitors by synthesizing analogues of lead candidates guided by the results of bulk crystallization assays and cell-based screening.This collaborative project will serve as a foundation for developing new therapeutics to prevent ammonium urate stone formation in both dolphins and humans. If the proposed research objectives are successful, the Navy will have a means not only to understand the basic mechanisms of stone formation in dolphins, but will also have a means of preventing and treating kidney stone disease in their dolphins. If implemented, it will have a major impact on the health, survival, and longevity of these military working animals. Approved for Public Release.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 06, 2021
- Source ID
- N000142112173
Entities
People
- Jeffrey D Rimer
Organizations
- Office of Naval Research
- United States Navy
- University of Houston System