Targeting Renal Purinergic Signaling for the Treatment of Lithium-induced NDI

靶向肾脏嘌呤信号传导治疗锂诱导的 NDI

基本信息

批准号：
8259070
负责人：
BELLAMKONDA K KISHORE
金额：
--
依托单位：
VA SALT LAKE CITY HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8259070
关键词：
Acute Adverse effects Affect Agonist Amiloride Anxiety Argipressin Biological Biological Models Bipolar Disorder Blood Cardiovascular system Cell Culture Techniques Cells Chemosensitization Chronic Clinical Clinical Trials Coagulation Process Combined Modality Therapy Conscious Culture Media Data Dehydration Development Drug Delivery Systems Duct (organ) structure Elderly Electrolytes Equilibrium Evaluation Event Formularies Freedom Functional disorder Funding Future General Population Genetic Goals Healthcare Hypernatremia Hypovolemia Infusion procedures Injection of therapeutic agent Intervention Intoxication Investigation Iraq Kidney Knock-out Knockout Mice Knowledge Laboratories Life Liquid substance Lithium Major Depressive Disorder Marines Marketing Mediating Mental Depression Methods Mission Modality Modeling Molecular Morbidity - disease rate Mus Nature Nephrogenic Diabetes Insipidus Nucleotides Outcome P2Y2 receptor PTGS2 gene Pathway interactions Patients Pharmaceutical Preparations Physiological Plavix Play Post-Traumatic Stress Disorders Prevalence Purinoceptor Rattus Receptor Gene Replacement Therapy Reporting Research Resistance Risk Role Safety Screening procedure Signal Transduction Soldier Staging Substance abuse problem Surveys System Techniques Therapeutic Therapeutic Agents Therapeutic Uses Tissue Sample Tissues Urine V2 Receptors Vasopressins Veterans Vietnam War Water Wild Type Mouse Work abstracting analog base clinical practice clinically relevant clopidogrel design extracellular feeding hemodynamics high risk improved in vivo infancy inhibitor/antagonist innovation insight meetings mortality novel older patient operation prevent purinoceptor P2Y4 receptor research study response social success suicidal risk urinary

项目摘要

DESCRIPTION (provided by applicant): 6. Project Summary/Abstract Nephrogenic diabetes insipidus (NDI) due to lithium therapy for bipolar disorder is one of the major nephrological problems among Veterans. NDI is a debilitating condition with an elevated risk of morbidity and even mortality, especially in elderly Veterans. Currently used therapeutic modalities for NDI are encountered with varying degrees of success as well as side effects, including lithium intoxication. Refinement and/or replacement of the current side effect-prone therapies with new drugs based on an improved understanding of molecular pathophysiology of lithium-induced NDI should result in improved efficacy and fewer side effects. Research carried out by us during the current funding period provided significant insights into the potential role of purinergic signaling in the genesis of lithium-induced NDI. These are: (i) purinergic signaling may play a potential overarching role in balancing the effect of arginine vasopressin (AVP) on the urinary concentration mechanism; (ii) in lithium-induced NDI, purinergic signaling in the medullary collecting duct is sensitized and involves more than one subtype of P2Y receptors; and (iii) P2Y2 receptor gene knockout mice are significantly resistant to the development of lithium-induced NDI, suggesting the potential role of purinergic signaling in the genesis of lithium-induced NDI. Based on our novel and significant observations we hypothesize that a deeper understanding of the role of renal purinergic signaling in Li-induced NDI offers better therapeutic modalities. A new class of drugs that target purinergic signaling may improve the safety and/or efficacy of the current medications in combination therapies, or replace them in the treatment of Li-induced NDI. The specific objective of the project are: 1) to investigate the role of purinergic signaling in the development of Li-induced AVP resistance using P2Y2 receptor knockout and wild type mice; 2) to investigate the role of purinergic signaling in Li-induced AVP resistance of medullary collecting duct using primary cultures of mouse inner medullary collecting duct cells; and 3) to investigate the effect of amiloride and COX-2 inhibition on Li-induced NDI in a background of blunted purinergic signaling. To achieve our objectives we will use P2Y2 receptor knockout mice, rats and cell culture models, and employ molecular, functional, immunohistochemical and cell signaling techniques. PUBLIC HEALTH RELEVANCE: 7. Project Narrative Post-traumatic stress disorder, often seen in Veterans, predisposes them to bipolar disorder. Currently there are more than 27 million Veterans, of which about 4% suffer from bipolar disorders. About 30% of bipolar Veterans receive lithium treatment, which is the drug of choice because of low suicidal risk in lithium treated patients. However, the therapeutic use of lithium is associated with a major side effect, called nephrogenic diabetes insipidus (NDI). NDI is associated with morbidity and even mortality, if not treated properly. Currently used medications for the treatment of NDI have side effects and may not be safe all patients. The observations made by us on the potential role of purinergic signaling in lithium-induced NDI at this VA facility opened an avenue for the development of better therapeutic modalities for the treatment of lithium-induced NDI. This grant application proposes studies to further strengthen these concepts.

描述（由申请人提供）： 6。由于双相情感障碍锂治疗引起的项目摘要/摘要肾病性糖尿病（NDI）是退伍军人的主要肾病问题之一。 NDI是一种令人衰弱的状况，发病率甚至死亡率升高，尤其是在老年退伍军人中。当前使用的NDI治疗方式遇到了不同程度的成功和副作用，包括锂中毒。基于对锂诱导的NDI的分子病理生理学的了解，将目前副作用疗法的细化和/或替换为新药，应提高疗效和更少的副作用。我们在当前的资金期间进行的研究为嘌呤能信号传导在锂诱导的NDI的起源中的潜在作用提供了重大见解。这些是：（i）嘌呤能信号传导在平衡精氨酸加压素（AVP）对尿液浓度机制的影响方面起潜在的总体作用；（ii）在锂诱导的NDI中，髓样收集导管中的嘌呤能信号传导敏感，涉及多种P2Y受体的亚型；（iii）P2Y2受体基因基因敲除小鼠对锂诱导的NDI的发展具有显着抗性，这表明嘌呤能信号传导在锂诱导的NDI的起源中的潜在作用。基于我们的新颖和重要的观察，我们假设对肾嘌呤能信号在Li诱导的NDI中的作用有更深入的了解提供了更好的治疗方式。靶向嘌呤能信号传导的一类新药物可以提高当前药物在联合疗法中的安全性和/或疗效，或取代它们在LI诱导的NDI治疗中。该项目的具体目标是：1）研究使用P2Y2受体敲除和野生型小鼠，研究嘌呤能信号传导在LI诱导的AVP抗性中的作用； 2）研究嘌呤能信号传导在LI诱导的髓样收集导管中使用小鼠内髓质收集管细胞的作用； 3）在钝化的嘌呤能信号传导的背景下，研究Amiloride和Cox-2抑制对LI诱导的NDI的影响。为了实现我们的目标，我们将使用P2Y2受体敲除小鼠，大鼠和细胞培养模型，并采用分子，功能，免疫组织化学和细胞信号传导技术。公共卫生相关性： 7。经常在退伍军人中看到的创伤后应激障碍，使他们容易受到双相情感障碍。目前，有超过2700万的退伍军人，其中约4％的人患有躁郁症。大约30％的双极退伍军人接受锂治疗，这是锂治疗的患者自杀风险低的选择。然而，锂的治疗用途与主要的副作用有关，称为肾脏基糖尿病（NDI）。 NDI与发病率甚至死亡率有关，即使没有得到适当的治疗。目前使用的NDI治疗药物具有副作用，并且可能不安全。我们对嘌呤能信号传导在锂诱导的NDI中的潜在作用的观察为开发了更好的治疗方式以治疗锂诱导的NDI的途径。该赠款应用建议的研究以进一步加强这些概念。