Chromium Mesoporphyrin in the Prevention of Neonatal Jaundice

铬中卟啉预防新生儿黄疸

基本信息

批准号：
7945355
负责人：
DAVID K STEVENSON
金额：
$ 36.25万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7945355
关键词：
Address Affect Bilirubin Biological Biological Assay Cell Death Cessation of life Clinical Clinical Research Disease Enzymes Erythema Evaluation Excretory function Extremely Low Birth Weight Infant Failure Free Radicals Future Genetic Transcription Heme Human Hyperbilirubinemia Icterus In Vitro Infant Kernicterus Kidney Laboratories Light Lipid Peroxidation Lipids Liver Long-Term Effects Membrane Messenger RNA Metabolic Metalloporphyrins Mining Modeling Monitor Monkeys Mus Neonatal Neonatal Jaundice Neurodevelopmental Impairment Newborn Animals Newborn Infant Operative Surgical Procedures Oral Oral Administration Oxygenases Pattern Pharmaceutical Preparations Phase III Clinical Trials Photosensitivity Photosensitization Photosensitizing Agents Phototherapy Phototoxicity Prevention Prevention approach Production Proteins Randomized Rattus Regulation Rh Isoimmunization Risk Safety Singlet Oxygen Skin Spleen Stress Therapeutic Therapeutic Agents Tissues War Work absorption alternative treatment analog base brain tissue chromium mesoporphyrin cytotoxicity design direct application enzyme activity heme a heme oxygenase-1 heme oxygenase-2 in vivo inhibitor/antagonist mortality mouse model neonate nonhuman primate pre-clinical public health relevance response therapeutic target tin mesoporphyrin treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Neonatal jaundice occurs in 60-70% of all newborn infants. It is caused not only by an overproduction of bilirubin, but also by a transient failure to excrete this metabolite. Hyperbilirubinemia is exacerbated by hemolytic diseases, such as Rhesus isoimmunization and ABO incompatibility, which result in increased bilirubin production, as well as diseases that result in decreased bilirubin excretion. The rate-limiting enzyme in the production of bilirubin is heme oxygenase (HO), and as such is a key therapeutic target. Inhibition of HO activity has been shown to protect newborns from excessive hyperbilirubinemia. Heme analogs, metalloporphyrins (Mps), are potent competitive inhibitors of HO enzyme activity. The use of Mps as oral therapeutic agents may be an effective approach for the prevention and treatment of hyperbilirubinemia. In this proposal, we will extend our preliminary studies of chromium mesoporphyrin (CrMP), which is a potent HO inhibitor, absorbable orally and photo-inert, in the newborn mouse. In anticipation of positive findings, we propose to extend these studies further to the non-human primate newborn model. In our laboratory, we have continued to develop and validate assays to monitor in vivo heme degradation and HO-1 transcriptional patterns and in vitro enzymatic activity of HO so that we can evaluate regulation and expression at these two levels. Application of these approaches to the neonatal mouse model is a natural extension of our work with the newborn rat, mouse, and monkey models. The results of this project will assist in the design of future clinical studies of CrMP by providing both spatial and temporal information pertaining to its direct effects on the enzymatic target, its expression, and subsequent short- and long-term effects on the newborn animal. The specific aims of this application are directed at evaluating the efficacy and safety of CrMP for the treatment of neonatal jaundice through inhibition of HO activity and serves as a basis for a "pre-clinical" IND evaluation of its potential efficacy and safety for use in the human neonate, with particular emphasis on short- and long-term effects in the heme-loaded newborn mouse. Use of a newborn mouse model should permit well-controlled systematic studies preceding the administration of CrMP, a very promising inhibitor, for the treatment of neonatal jaundice. PUBLIC HEALTH RELEVANCE: Heme oxygenase (HO) is a key therapeutic target in the prevention of neonatal jaundice. We have been investigating the efficacy and safety of metalloporphyrins (Mps) for their potential use in the treatment of neonatal jaundice. In this proposal, we propose to extend our studies of CrMP in the mouse because CrMP is a potent HO inhibitor, absorbable orally and photo-inert. The specific aims of this application serve as a basis for a "pre-clinical" IND evaluation of potential efficacy and safety of CrMP for use in the human neonate, with particular emphasis on short- and long-term effects in the heme-loaded newborn mouse.

描述（由申请人提供）： 60-70% 的新生儿患有新生儿黄疸。它不仅是由于胆红素产生过多引起的，而且也是由于暂时无法排出这种代谢物引起的。高胆红素血症因溶血性疾病而加剧，例如恒河猴同种免疫和 ABO 血型不合，导致胆红素产生增加，以及导致胆红素排泄减少的疾病。胆红素产生的限速酶是血红素加氧酶 (HO)，因此是一个关键的治疗靶点。抑制 H2O2 活性已被证明可以保护新生儿免受过多的高胆红素血症的影响。血红素类似物金属卟啉 (Mps) 是 H2O 酶活性的有效竞争性抑制剂。使用Mps作为口服治疗剂可能是预防和治疗高胆红素血症的有效方法。在本提案中，我们将在新生小鼠中扩展对铬中卟啉 (CrMP) 的初步研究，CrMP 是一种有效的 H2O 抑制剂，可口服吸收且具有光惰性。期待积极的发现，我们建议将这些研究进一步扩展到非人类灵长类新生儿模型。在我们的实验室中，我们继续开发和验证检测方法来监测体内血红素降解和 HO-1 转录模式以及 HO 的体外酶活性，以便我们可以评估这两个水平的调节和表达。这些方法在新生小鼠模型中的应用是我们在新生大鼠、小鼠和猴子模型方面工作的自然延伸。该项目的结果将通过提供有关 CrMP 对酶靶点的直接影响、其表达以及随后对新生动物的短期和长期影响的空间和时间信息，帮助设计 CrMP 的未来临床研究。本申请的具体目的是评估 CrMP 通过抑制 HO 活性来治疗新生儿黄疸的功效和安全性，并作为“临床前”IND 评估其潜在功效和安全性的基础。人类新生儿，特别强调对血红素负载的新生小鼠的短期和长期影响。使用新生小鼠模型应该可以在使用 CrMP（一种非常有前途的抑制剂）治疗新生儿黄疸之前进行良好控制的系统研究。公共卫生相关性：血红素加氧酶 (HO) 是预防新生儿黄疸的关键治疗靶点。我们一直在研究金属卟啉 (Mps) 在治疗新生儿黄疸方面的潜在用途的有效性和安全性。在本提案中，我们建议在小鼠中扩展 CrMP 的研究，因为 CrMP 是一种有效的 H2O 抑制剂，可口服吸收且具有光惰性。该申请的具体目标是对 CrMP 用于人类新生儿的潜在功效和安全性进行“临床前”IND 评估的基础，特别强调对血红素负载新生儿的短期和长期影响老鼠。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of light exposure on metalloporphyrin-treated newborn mice.

光暴露对金属卟啉治疗的新生小鼠的影响。

DOI：
发表时间：
2012-08
期刊：
影响因子：
3.6
作者：
Schulz, Stephanie;Wong, Ronald J;Kalish, Flora S;Zhao, Hui;Jang, Kyu Yun;Vreman, Hendrik J;Stevenson, David K
通讯作者：
Stevenson, David K