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）是一种已确立的双相情感障碍治疗方法，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，锂疗法的一个显著副作用是肾源性尿崩症（NDI）。锂诱导的NDI归因于髓集合管（mCD）产生的前列腺素E2（PGE 2）增加。目前旨在直接抑制Li诱导的NDI中PGE 2合成的疗法遇到严重的副作用，包括Li中毒。基于对Li诱导的NDI的分子病理生理学的更好理解，用新的药物替代当前的副作用倾向性药物，应该会提高临床疗效，减少副作用。在这种情况下，我们发现，在锂诱导的NDI中，肾脏PGE 2的产生增加可能与髓集合管（mCD）中的细胞外核苷酸（ATP/UTP）受体P2 Y 2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（可溶性外核苷酸酶）可显著减少锂诱导的多尿，这与mCD增加P2 Y2受体激动剂刺激的PGE 2释放的正常化有关。我们还发现，P2 Y2受体的基因缺失导致对锂诱导的多尿的发展具有显著的抗性。基于这些发现，该提议的中心假设是，超敏反应和通过P2 Y2受体增强的信号传导通过显著增加mCD产生的PGE 2在体内Li诱导的NDI的发展中起重要作用。我们进一步提出，天然和工程外核苷酸酶的细胞外核苷酸的治疗性清除应提供一个有效的和更安全的方法治疗锂诱导的NDI。具体目的是：（i）确定细胞外核苷酸的组成性清除是否减弱Li诱导的NDI的发展。为了实现这一目标，我们将使用CD 39（NTPDase 1，一种外核苷酸酶）过表达转基因小鼠模型;（ii）确定是否药理清除细胞外核苷酸的天然或工程可溶性NTPDases管理将改善锂诱导的大鼠多尿。该提案的长期目标是开发基于通过清除细胞外核苷酸特异性阻断P2 Y2受体活性的方法的锂诱导的NDI的创新疗法。 公共卫生关系：锂是治疗双相情感障碍的有效药物，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，近年来锂已被确定为治疗急性和慢性神经退行性疾病（如中风或阿尔茨海默氏症）的有效药物。然而，锂的使用与对肾脏的不良副作用相关-诱发尿崩症或水糖尿病。目前用于治疗尿崩症的疗法遇到严重的副作用，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，以开发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