Role of Ectonucleotidase in Voiding Function and Dysfunction

外切核苷酸酶在排尿功能和功能障碍中的作用

• 批准号: 10453611
• 负责人: weiqun yu
• 金额: $ 38.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-19 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453611
• 关键词: ATP Hydrolysis; Address; Adenosine; Adrenergic Agents; Affect; Age; Aging; Agonist; Appearance; Atropine; Autoimmune; Autoimmune Diseases; Bladder; Bladder Control; Bladder Diseases; Bladder Dysfunction; Bladder Tissue; Clinical; Comparative Study; Cost of Illness; Data; Diabetes Mellitus; Disease; Drug Targeting; Enzymes; Exhibits; Functional disorder; Genes; Human; Impairment; Kinetics; Knock-out; Knockout Mice; Knowledge; Light; LoxP-flanked allele; Mediating; Mediator of activation protein; Molecular; Mouse Strains; Mus; Muscarinic Antagonists; Muscarinics; Mutation; Myocardium; Nature; Nerve; Neurodegenerative Disorders; Overactive Bladder; Partner in relationship; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Physiology; Play; Population; Purinoceptor; Receptor Signaling; Regulation; Relaxation; Reporting; Research; Rodent; Role; Seeds; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; Symptoms; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Translating; Urination; Visceral; cost; design; diabetic; differential expression; disabling symptom; health related quality of life; human disease; human female; insight; loss of function mutation; lower urinary tract symptoms; male; mouse model; mutant mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; prevent; receptor; receptor expression; receptor function; sex; social; telokin

Abstract: Lower urinary tract symptoms (LUTS) impact a large percentage of the population with enormous financial and social costs, and effective drugs for management of LUTS are limited. Purinergic signaling is a prominent dysregulated pathway, which has been consistently reported in LUTS. While purinergic contractility is minimal in normal human bladder, it increases significantly in bladders of human patients, to more closely resembles documented rodent physiology. However, the underlying mechanism which results in these functional pathway alterations is not known. To study this, we have identified multiple novel functional purinergic receptors and modulators in bladder. We have demonstrated that purinergic signaling is not only important for contraction in bladder wall, as mediated by ATP/ADP activated P2X1/P2Y12 signaling, but is also important for bladder relaxation mediated by adenosine activated A2b receptor signaling. Furthermore, A2b receptor mediated relaxation signaling can completely inhibit P2X1/P2Y12 mediated contractions. By comparative studies, we have defined a key gene - ENTPD1 (also known as CD39) – that is differentially expressed in human and mouse bladders (~ 8-fold higher in normal human bladders than in mouse). ENTPD1 is a rate-limiting enzyme converting ATP/ADP/AMP sequentially. ENTPD1 controls the kinetics of an agonist cascade (ATP>ADP>adenosine), and hence plays a critical role in the control of purinergic receptor expression and function. Interestingly, human ENTPD1 mutations have been identified in autoimmune diseases and neurodegenerative disorders, and LUTS is a prominent symptom in these diseases. Consistent with this, impaired ATP hydrolysis has been reported in bladder tissues from LUTS patients. Therefore, we hypothesize that ENTPD1 is a key regulator in bladder function. In support, we have preliminary data from a global Entpd1- /- mouse, indicating that deletion of Entpd1 results in a dilated bladder with abnormal voiding phenotype. We will test our hypothesis through the following aims: (1) We will generate a visceral smooth muscle specific Entpd1 knockout mouse model to demonstrate the critical importance of ENTPD1 in regulating normal detrusor contractility and bladder function; (2) We will use two ENTPD1 mutant mouse models with high and low ENTPD1 expression levels to mimic human bladders that are normal (high) and diseased (low), and then examine voiding function/dysfunction; (3) Through the National Disease Research Interchange (NDRI) network, we will procure human bladder tissues, and study the expression and function of ENTPD1 in the bladders of both sexes. We will solve the puzzles of why there are purinergic contractile differences between human and rodent bladders, between male and female human bladders, and between normal and diseased human bladders. We expect this study to substantially advance our understanding on how bladder contraction and relaxation is controlled by ENTPD1 and its associated purinergic signaling. These studies have high potential to introduce novel therapies for human LUTS patients as there are multiple targetable options.

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