Potential Therapeutic Applications of Ecto-Nucleotidases in Lithium-induced NDI

外切核苷酸酶在锂诱导 NDI 中的潜在治疗应用

基本信息

批准号：
7660114
负责人：
BELLAMKONDA K KISHORE
金额：
$ 20.89万
依托单位：
WESTERN INSTITUTE FOR VETERANS RESEARCH
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：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7660114
关键词：
Acute Adverse effects Affect Agonist Alzheimer&apos s Disease Anabolism Animal Model Apyrase Area Argipressin Binding Bipolar Disorder Characteristics Chronic Clinic Cyclic AMP Development Diabetes Insipidus Diabetes Mellitus Dinoprostone Duct (organ) structure Engineering Exhibits Functional disorder Future General Population Generations Genetic Goals Huntington Disease Hypersensitivity Indomethacin Innovative Therapy Intoxication Investigation Kidney Knockout Mice Lithium Methods Modeling Molecular NIH Program Announcements Nephrogenic Diabetes Insipidus Neurodegenerative Disorders Nucleotides P2Y2 receptor Parkinson Disease Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Play Polydipsia Polyuria Principal Investigator Production Prostaglandin-Endoperoxide Synthase Proteins Rattus Recombinants Research Resistance Role Signal Transduction Sprague-Dawley Rats Stroke Therapeutic Therapeutic Uses Time Transgenic Mice Urine Veterans Water aquaporin-2 base clinically significant ecto-nucleotidase ectoADPase extracellular improved in vivo mouse model mutant novel programs public health relevance suicidal risk uridine triphosphate receptors water flow

项目摘要

DESCRIPTION (provided by applicant): Lithium (Li), an established treatment for bipolar disorders, is emerging as a potential neuroprotective therapy for acute and chronic neurodegenerative diseases. However, a significant side effect of Li therapy is nephrogenic diabetes insipidus (NDI). Li-induced NDI has been attributed to increased production of prostaglandin E2 (PGE2) by the medullary collecting duct (mCD). Current therapies aimed at direct inhibition of PGE2 synthesis in Li-induced NDI are encountered with serious side effects, including Li intoxication. Replacement of the current side effect-prone drugs with new ones based on improved understanding of molecular pathophysiology of Li-induced NDI should result in improved efficacy and fewer side effects in the clinic. In this context, we discovered that increased production of renal PGE2 in Li-induced NDI may be related to the hypersensitivity of P2Y2 receptor, an extracellular nucleotide (ATP/UTP) receptor, in the medullary collecting duct (mCD). Preliminary studies conducted in rat model showed that administration of apyrase (soluble ecto-nucleotidase) causes significant reduction in Li-induced polyuria, associated with normalization of the augmented release of P2Y2 receptor agonist-stimulated PGE2 release by the mCD. We also found that genetic deletion of P2Y2 receptor results in marked resistance to the development of Li-induced polyuria. Based on these findings, the central hypothesis of this proposal is that hypersensitivity and enhanced signaling through P2Y2 receptor plays a significant role in vivo in the development of Li-induced NDI by markedly increasing the production of PGE2 by the mCD. We further propose that therapeutic scavenging of the extracellular nucleotides by native and engineered ecto-nucleotidases should offer an efficacious and safer approach for the treatment of Li-induced NDI. The specific aims are: (i) to determine whether constitutive scavenging of extracellular nucleotides blunts the development of Li-induced NDI. To achieve this goal, we will use CD39 (NTPDase1, an ecto-nucleotidase) over expressing transgenic mouse model; and (ii) to determine whether pharmacological scavenging of extracellular nucleotides by the administration of native or engineered soluble NTPDases will ameliorate the Li-induced polyuria in rats. The long-term objective of this proposal is to develop innovative therapies for Li-induced NDI based on the approach of specific blockade of the activity of P2Y2 receptor by scavenging the extracellular nucleotides. PUBLIC HEALTH RELEVANCE: Lithium is an effective drug for the treatment of bipolar disorders, which affect about 2-3% of general population and 4-6% of Veterans. In addition to its long-standing use for the treatment of bipolar disorders, in recent years lithium has been identified as a potent drug for the treatment of acute and chronic neurodegenerative disorders, such as stroke or Alzheimer's, respectively. However, the use of lithium is associated with adverse side effect on the kidney - induction of diabetes insipidus or water diabetes. Current therapies for the treatment of diabetes insipidus are encountered with serious side effects, including lithium intoxication. This project, which identifies novel molecular pathways that may be responsible for the excessive loss of water and salt, proposes to further investigate these pathways with a possibility to develop innovative therapies for use in the clinic.

描述（由申请人提供）：锂（Li）是一种已建立的双相疾病的治疗方法，正在成为一种潜在的急性和慢性神经退行性疾病的神经保护疗法。然而，李治疗的显着副作用是肾脏基糖尿病（NDI）。 Li诱导的NDI归因于髓质收集导管（MCD）增加前列腺素E2（PGE2）的产生。旨在直接抑制LI诱导的NDI中PGE2合成的当前疗法遇到了严重的副作用，包括Li中毒。基于对LI诱导的NDI的分子病理生理学的了解，将当前副作用的药物替换为新药物，应提高疗效的疗效和较少的副作用。在这种情况下，我们发现在Li诱导的NDI中增加的肾脏PGE2的产生可能与髓外核苷酸（ATP/UTP）受体P2Y2受体的超敏反应有关，在髓质收集导管中（MCD）。在大鼠模型中进行的初步研究表明，丙酶的给药（可溶性核苷酸酶）导致Li诱导的多尿症显着降低，这与MCD的P2Y2受体激动剂刺激的PGE2释放的增强释放有关。我们还发现，P2Y2受体的遗传缺失导致对Li诱导的多尿的发展有明显的抵抗力。基于这些发现，该提议的中心假设是，通过P2Y2受体通过P2Y2受体增强信号传导在体内在LI诱导的NDI的发展中起着重要作用，通过显着增加MCD的PGE2产生。我们进一步提出，天然和工程性核苷酸酶对细胞外核苷酸的治疗清除应提供有效，更安全的方法来治疗LI诱导的NDI。具体目的是：（i）确定构型清除细胞外核苷酸的清除是否会钝化LI诱导的NDI的发展。为了实现这一目标，我们将使用表达转基因小鼠模型的CD39（NTPDase1，Ecto-核苷酸酶）。（ii）确定通过给予天然或工程可溶性NTPDase对细胞外核苷酸的药理清除是否会改善大鼠的LI诱导的多尿症。该提案的长期目标是基于通过清除细胞外核苷酸的特定封锁P2Y2受体活性的方法来开发对Li诱导的NDI的创新疗法。公共卫生相关性：锂是治疗双相情感障碍的有效药物，影响了约2-3％的普通人群和4-6％的退伍军人。除了长期用于治疗双极疾病外，近年来，锂还被确定为治疗急性和慢性神经退行性疾病的有效药物，例如中风或阿尔茨海默氏症。然而，锂的使用与副作用对肾脏的不利副作用有关 - 诱导糖尿病或水糖尿病。遇到严重的副作用，包括锂醉酒，遇到严重的副作用。该项目确定了可能导致水和盐过度损失的新分子途径，建议进一步研究这些途径，并有可能开发创新的疗法以在诊所使用。