Mechanisms of heavy metal-induced disease and therapeutic strategies

重金属诱发疾病的机制及治疗策略

• 批准号: 10517910
• 负责人: Matthew J Campen
• 金额: $ 4.55万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-14 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517910
• 关键词: Attenuated; Award; Biological; Cell physiology; Center for Translational Science Activities; Chelating Agents; Chelation Therapy; Cities; Clinical Research; Clinical Sciences; Collaborations; Complex; Contrast Media; Data; Development; Diagnostic; Discipline; Disease; Elements; Exposure to; Foundations; Gadolinium; Geography; Goals; Health; Health Sciences; Health system; Healthcare Systems; Heavy Metals; Hispanic; Hospitals; Informatics; Institutional Policy; Investigation; Kidney; Label; Lanthanoid Series Elements; Lead; Leadership; Learning; Liver; Longevity; Magnetic Resonance Imaging; Measures; Medical; Membrane; Metals; Methods; Minority; Molecular; Nanostructures; Native Americans; Nephrogenic Systemic Fibrosis; Nervous system structure; New Mexico; Organ; Outcome; Parents; Patients; Phase; Play; Policy Developments; Population; Process; Renal function; Reporting; Research; Research Design; Research Methodology; Resource Sharing; Resources; Rodent Model; Role; Rural; Site; Skin; Special Population; Speed; Strategic Planning; Symptoms; Tail; Therapeutic; Therapeutic Uses; Toxic effect; Training; Training and Education; Translating; Translational Research; Translations; Universities; Vision; base; care outcomes; catalyst; chemical property; clinical center; cytotoxicity; effective therapy; ethnic diversity; health disparity populations; imaging agent; improved; in vivo; innovation; nanoscale; novel diagnostics; physical property; preventive intervention; prophylactic; racial and ethnic; rural underserved; success; synergism; therapeutic development; therapeutic target

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.

获奖摘要 我们对新墨西哥州大学健康科学中心（UNM）临床和转化科学的愿景 中心（CTSC）将成为紧密集成网络的重要组成部分。由此产生的集体协同作用将 促进治疗、诊断和预防干预措施的过渡;传播创新的翻译 研究方法和最佳实践;并领导信息学标准和政策的制定，以促进共享 资源和临床和转化研究（CTR）。我们将通过提供跟踪资源来实现这一目标， 加快翻译，这将与其他CTSA中心协调，例如：多中心研究 支持，监管支持，研究设计，劳动力培训和综合信息支持。我们的重点 将推进临床和转化研究与科学（CTR/S）的全方位发展。使我们 我们还提出了有意义的、可衡量的目标和成果。UNM CTSC 提供了一个独特的设置，以实现这一愿景，并促进高质量的CTR/S。四个少数民族之一 在美国，新墨西哥州是种族多元化（盎格鲁，西班牙裔，美洲原住民），农村，医疗剥夺 with health-disparate健康distinctive不同populations人群.我们的州在地理、种族/民族和农村方面对医疗保健存在障碍 和结果，并且是24个拥有CTSC中心的IDEA州中仅有的5个。CTSC的一个关键要素是 持续改进和学习，以便将我们所知道的转化为我们所做的。为了实现 为此，我们将继续建立和加强新技术能力之间的协同作用，促进机会， 并影响机构政策的改变。通过以下五个战略目标，我们准备发挥领导作用 在我们的国家和地区的作用，同时是一个重要的资产，并在CTSA财团的合作伙伴：1）调整 整个UNM卫生系统，其合作伙伴及其学术的治理，领导和战略规划 企业与CTSC和CTR/S; 2）参与有益的合作和伙伴关系; 3）使用我们的初始 在教育和培训方面取得成功，以建立明天的翻译队伍; 4）开发和传播 创新和精简的研究资源（包括数据和信息学），方法和流程， 专注于质量和效率; 5）将翻译科学的多个阶段和学科整合在 复杂的人群和整个生命周期。有了我们的CTSC作为催化剂，我们的预期成果是a） 通过持续的投入、创新和学习来改善健康状况; B）加快新技术的开发和使用 诊断、治疗、预防性干预;以及c）关注我们国家的复杂和特殊人群 国家和地区，包括那些农村，服务不足，在整个生命周期的多样性。 项目摘要 基于钆（Gd）的造影剂导致有时致命且通常使人衰弱的“肾源性” 全身性纤维化（NSF）。镧系元素Gd独特的物理和化学性质使其具有重金属的特性。 金属是诊断性磁共振成像（MRI）和靶向纳米级疗法中不可或缺的重要组成部分。 暴露于这些MRI造影剂后，已证实靶器官中存在Gd蓄积， 包括患者的肾脏、皮肤、肝脏和神经系统（许多肾功能正常）。50%左右 所有MRI检查中的10%都用钆增强。环境Gd与环境Gd之间存在明显的相关性， 浓度和医疗保健系统的水平，因为在大城市附近发现过量的Gd水平， 做核磁共振的医院Gd-螯合物并不像预期的那样稳定，因为许多患者报告了不同的范围 症状归因于先前的钆暴露。我们的研究团队已经建立了一个良好的- 钆诱导疾病的特征性啮齿动物模型。我们是第一个报告体内形成的 通过使用磁共振成像造影剂的全身治疗产生的纳米结构。 对保留钆的复杂性的调查是有限的。定义这种生物效应 镧系元素是最重要的。 这一补充将集中在定义钆诱导的细胞和分子扰动，旨在 开发安全有效的治疗方法，以减轻镧系元素引起的疾病的并发症。这一目标将 通过发展重金属钆如何与 生物膜，导致细胞毒性，以及如何预防性或事后使用治疗靶点， 减弱Gd滞留。这一补充将为我们提供审查的影响， 金属滞留细胞过程，确定治疗目标，并提供一个基础 了解钆诱导的毒性。确定这些方法和疗法符合 新墨西哥州大学健康科学中心临床和转化科学中心家长奖。