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.

家长奖摘要 我们对新墨西哥大学健康科学中心（UNM）临床和转化科学的愿景 中心（CTSC）是紧密整合网络的重要组成部分。由此产生的集体协同作用将 催化治疗，诊断和预防性干预措施的过境；传播创新的翻译 研究方法和最佳实践；并领导信息标准和政策制定以促进共享 资源，临床和翻译研究（CTR）。我们将通过提供尾声的资源来实现这一目标 加速翻译将与其他CTSA集线器协调，包括：多站点研究 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 将促进临床和翻译研究与科学（CTR/S）的全部范围。这样我们 影响明确证明了影响，我们还提出了有意义的，测量的目标和结果。 UNM CTSC 提供了一个独特的环境来实现这一愿景并催化高质量的CTR/S。四个多数人之一 国家，新墨西哥州是种族的潜水员（盎格鲁，西班牙裔，美国原住民），粗暴而医学上被剥夺了权利 与健康的人群。我们的州提出了地理，种族/种族和医疗保健的粗糙障碍 和结果，是具有CTSC中心的24个想法状态中的五个。我们CTSC的关键要素是 持续的改进和学习，以将我们知道的知识转化为我们的工作。为了实现 这，我们将继续在新的技术能力中建立和增强协同作用，催化机会， 并影响机构政策的改变。通过以下五个战略目标，我们被毒死了 在我们的州和地区的角色，同时成为CTSA联盟中的重要资产并合作：1）对齐 整个UNM卫生系统，其合作伙伴及其学术的治理，领导和战略计划 具有CTSC和CTR/S的企业； 2）进行有益的合作和伙伴关系； 3）使用我们的最初 在教育和培训方面取得成功，以建立明天的转化劳动力； 4）发展和传播 具有创新和简化的研究资源（包括数据和信息范围），方法和流程 专注于质量和效率； 5）在其多个阶段和学科中整合转化科学 复杂的人群以及整个寿命。以我们的CTSC作为催化剂，我们的预期结果是A） 通过持续的投入，创新和学习来改善健康； b）加快新的开发和使用 诊断，治疗，预防性干预措施； c）专注于我们的复杂和特殊人群 国家和地区，包括在整个寿命连续体内的粗糙，服务不足和潜水员的国家和地区。 项目摘要 基于Gadolinium（GD）的对比剂有时会导致肾小球且经常使人衰弱 全身纤维化（NSF）。灯笼元素GD的独特物理和化学特性使重量 对于诊断磁共振成像（MRI）和靶向纳米级疗法的高度必不可少的金属。 暴露于这些MRI对比剂后，在目标器官中已证明了GD蓄能 包括患者的肾脏，皮肤，肝脏和神经系统（许多肾功能正常）。约50％ 在所有MRI检查中，Gadolinium都会增强。环境GD之间存在明显的相关性 在靠近大城市的浓度和医疗系统水平以上 医院表演MRI。 GD-Chelates不如许多患者报告的潜水员范围那样稳定 归因于先前的gadolin暴露的符号。我们的研究团队已经建立了一个很好的 特征的啮齿动物模型的gadolin诱导疾病。我们是第一个报告体内形成的人 通过磁共振成像对比剂的全身处理产生的纳米结构。 对保留的gadolium的复杂性的调查是有限的。定义生物学效应 灯笼是至关重要的。 该补充剂将着重于定义涉及宗教的细胞和分子扰动 开发安全有效的疗法，以减轻兰谷诱导的疾病并发症。这个目标将 通过对重金属gadolium如何与 生物膜，导致细胞毒性以及治疗靶标的预防或事后使用 衰减GD保留。这种补充剂将使我们能够检查沉重的影响 金属在细胞过程上保留，识别治疗靶标并提供基础 了解gadolin诱导的毒性。确定此类方法和疗法与 新墨西哥大学健康科学中心临床和转化科学中心父母奖。