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

• 批准号: 7878061
• 负责人: BELLAMKONDA K KISHORE
• 金额: $ 16.64万
• 依托单位: WESTERN INSTITUTE FOR VETERANS RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878061
• 关键词: Acute; Adverse effects; Affect; Agonist; Alzheimer' 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

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) 是双相情感障碍的一种既定治疗方法，正在成为急性和慢性神经退行性疾病的潜在神经保护疗法。然而，Li疗法的一个显着副作用是肾性尿崩症（NDI）。 Li 诱导的 NDI 归因于髓质集合管 (mCD) 产生的前列腺素 E2 (PGE2) 增加。目前旨在直接抑制 Li 诱导的 NDI 中 PGE2 合成的疗法遇到了严重的副作用，包括 Li 中毒。基于对锂诱导 NDI 分子病理生理学的深入了解，用新药物替代目前容易产生副作用的药物，应该会提高临床疗效并减少副作用。在这种情况下，我们发现Li诱导的NDI中肾脏PGE2的产生增加可能与髓质集合管（mCD）中P2Y2受体（一种细胞外核苷酸（ATP/UTP）受体）的超敏性有关。在大鼠模型中进行的初步研究表明，给予腺苷三磷酸双磷酸酶（可溶性核酸外切酶）可显着减少锂诱导的多尿，这与 mCD 刺激的 P2Y2 受体激动剂刺激的 PGE2 释放的增加正常化有关。我们还发现 P2Y2 受体的基因缺失会导致对锂诱导的多尿症的发展产生明显的抵抗力。基于这些发现，该提议的中心假设是，通过 P2Y2 受体的超敏性和增强的信号传导在体内通过显着增加 mCD 产生的 PGE2 在 Li 诱导的 NDI 的发展中发挥着重要作用。我们进一步提出，通过天然和工程化的核酸外切酶对细胞外核苷酸的治疗性清除应该为治疗锂诱导的 NDI 提供有效且更安全的方法。具体目标是：（i）确定细胞外核苷酸的组成型清除是否会阻碍锂诱导的 NDI 的发展。为了实现这一目标，我们将使用CD39（NTPDase1，一种核酸外切酶）过表达转基因小鼠模型； (ii) 确定通过施用天然或工程化的可溶性 NTPDase 来药理学清除细胞外核苷酸是否会改善 Li 诱导的大鼠多尿症。该提案的长期目标是基于通过清除细胞外核苷酸特异性阻断 P2Y2 受体活性的方法，开发锂诱导的 NDI 的创新疗法。 公共健康相关性：锂是治疗双相情感障碍的有效药物，该疾病影响约 2-3% 的普通人群和 4-6% 的退伍军人。除了长期用于治疗双相情感障碍外，近年来，锂还被确定为分别治疗急性和慢性神经退行性疾病（例如中风或阿尔茨海默病）的有效药物。然而，锂的使用会对肾脏产生不良副作用 - 诱发尿崩症或水糖尿病。目前治疗尿崩症的疗法会遇到严重的副作用，包括锂中毒。该项目确定了可能导致水和盐过度流失的新分子途径，建议进一步研究这些途径，并有可能开发出用于临床的创新疗法。

项目成果

Defective renal water handling in transgenic mice over-expressing human CD39/NTPDase1.

过度表达人 CD39/NTPDase1 的转基因小鼠肾水处理缺陷。

• DOI: 10.1152/ajprenal.00060.2012
• 发表时间: 2012
• 期刊: American journal of physiology. Renal physiology
• 作者: Zhang,Yue;Morris,KaiyaL;Sparrow,ShannonK;Dwyer,KarenM;Enjyoji,Keiichi;Robson,SimonC;Kishore,BellamkondaK
• 通讯作者: Kishore,BellamkondaK

Impaired natriuretic response to high-NaCl diet plus aldosterone infusion in mice overexpressing human CD39, an ectonucleotidase (NTPDase1).

过度表达人 CD39（一种核酸外切酶 (NTPDase1)）的小鼠对高 NaCl 饮食加醛固酮输注的利尿钠反应受损。

• DOI: 10.1152/ajprenal.00125.2014
• 发表时间: 2015
• 期刊: American journal of physiology. Renal physiology
• 作者: Zhang,Yue;Robson,SimonC;Morris,KaiyaL;Heiney,KristinaM;Dwyer,KarenM;Kishore,BellamkondaK;Ecelbarger,CarolynM
• 通讯作者: Ecelbarger,CarolynM