Mechanisms of heavy metal-induced disease and therapeutic strategies

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PARENT AWARD SUMMARY Our vision for the University of New Mexico Health Science Center (UNM) Clinical and Translational Science Center (CTSC) is to be an essential part of tightly integrated networks. The resulting collective synergy will catalyze transit of therapeutic, diagnostic, and preventative interventions; disseminate innovative translational research methods and best practices; and lead informatics standards and policy development to promote shared resources and clinical and translational research (CTR). We will accomplish this by providing tailed resources to accelerate translation, which will be harmonized with other CTSA hubs, including for example: multi-site study support, regulatory support, research design, workforce training, and integrated informatics support. Our focus will be to advance the full spectrum of both clinical and translational research and science (CTR/S). So that our impact is clearly demonstrated, we also propose meaningful, measureable goals and outcomes. The UNM CTSC offers a unique setting to achieve this vision and to catalyze high quality CTR/S. One of four majority-minority states, New Mexico is ethnically diverse (Anglo, Hispanic, Native American), rural, and medically disenfranchised with health-disparate populations. Our state presents geographic, racial/ethnic, and rural obstacles to health care and outcomes and is among only five of 24 IDeA states with a CTSC hub. A key element of our CTSC is continuous improvement and learning in order to translate what we know into what we do. In order to achieve this, we will continue to build and enhance synergy among new technological capabilities, catalyze opportunities, and effect institutional policy change. Through the following five strategic aims, we are poised to play a leadership role in our state and region while being a significant asset to and partner in the CTSA consortium: 1) Align the governance, leadership, and strategic planning of the entire UNM health system, its partners, and its academic enterprise with the CTSC and CTR/S; 2) Engage in beneficial collaboration and partnerships; 3) Use our initial success in education and training to build the translational workforce of tomorrow; 4) Develop and disseminate innovative and streamlined research resources (including data and informatics), methods, and processes with a focus on quality and efficiency; 5) Integrate translational science across its multiple phases and disciplines within complex populations and across the lifespan. With our CTSC as the catalyst, our expected outcomes are to a) improve health through continuous input, innovation, and learning; b) speed the development and use of new diagnostics, therapeutics, preventative interventions; and c) focus on complex and special populations in our state and region, including those that are rural, underserved, and diverse across the continuum of lifespan. PROJECT SUMMARY Gadolinium (Gd)-based contrast agents cause the sometimes-lethal and often debilitating ‘nephrogenic’ systemic fibrosis (NSF). The unique physical and chemical properties of lanthanide element Gd render the heavy metal highly indispensable for diagnostic magnetic resonance imaging (MRI) and targeted nanoscale therapies. Following exposure to these MRI contrast agents, Gd-accumulation has been demonstrated in target organs, including the kidney, skin, liver, and nervous system of patients (many with normal renal function). Around 50% of all MRI exams are enhanced with gadolinium. There is a distinct correlation between environmental Gd concentrations and the level of healthcare systems as excess Gd levels are found in proximity to large cities with hospitals performing MRI. Gd-chelates are not as stable as anticipated as many patients report a diverse range of symptoms attributed to previous gadolinium exposures. Our research team has established a well- characterized rodent model of gadolinium-induced disease. We were the first to report the in vivo formation of nanostructures resulting from systemic treatment with magnetic resonance imaging contrast agents. Investigations into the complexities of retained gadolinium are limited. Defining the biological effect of this lanthanide is paramount. This supplement will focus on defining gadolinium-induced cellular and molecular perturbations aimed at developing safe and effective therapies to mitigate complications of lanthanide-induced diseases. This goal will be accomplished by developing a methodical understanding of how heavy metal gadolinium interacts with biological membranes, leads to cytotoxicity and how prophylactic or post-hoc use of therapeutic targets can attenuate Gd retention. This supplement will provide us with the ability to examine the impact of heavy metal retention on cellular processes, identify therapeutic targets, and provide a foundational understanding of gadolinium-induced toxicity. Identifying such methods and therapies align with the University of New Mexico Health Sciences Center Clinical and Translational Sciences Center Parent Award.