The neuropilin 2 axis in smooth muscle contractility

平滑肌收缩力中的神经毡蛋白 2 轴

• 批准号: 9127579
• 负责人: Rosalyn M Adam
• 金额: $ 53.59万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-13 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127579
• 关键词: Ablation; Adverse effects; Aging; Agonist; Agreement; Biochemical; Bladder; Bladder Control; Cholinesterase Inhibitors; Chronic; Clinical; Clinical Management; Clinical Treatment; Complex; Data; Diabetes Mellitus; Disease; Etiology; Evaluation; Financial cost; Functional disorder; Gene Deletion; Genetic; Genetically Engineered Mouse; Goals; Healthcare; Human; Impairment; In Vitro; Incontinence; Integral Membrane Protein; Investigation; Knock-out; Lead; Ligands; Lower urinary tract; Mediating; Medical; Mental Depression; Modeling; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; Muscle; Muscle Contraction; Muscle relaxation phase; Myosin Light Chains; Neuropilin-2; Neurotransmitters; Obstruction; Organ; Parasympathomimetic Agents; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Phosphorylation; Physiological; Physiology; Productivity; Publishing; Randomized Controlled Trials; Recurrence; Regulation; Relaxation; Rho-associated kinase; Role; Secondary to; Semaphorins; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Myocytes; Social isolation; Specimen; Symptoms; Testing; Therapeutic; Tissues; Urinary Retention; Urinary tract infection; base; body system; cost; in vivo; lower urinary tract symptoms; mouse model; neuromuscular; novel; public health relevance; social; systematic review; urolithiasis; urologic

 DESCRIPTION (provided by applicant): Bladder function depends on cycles of smooth muscle (SM) contraction and relaxation to achieve voiding and storage, respectively. Impairment of the strength or duration of bladder SM contraction characterizes a prevalent but poorly understood clinical condition termed detrusor underactivity (DU). DU is a complex disorder that (i) arises from diverse neuromuscular insults, including chronic bladder outlet obstruction, aging and persistent diabetes; (ii) reduces voiding efficiency and (iii) can lead to significant urologic complications. Irrespective of etiology, the loss of normal bladder contractilty in DU is a serious clinical problem that is not understood in mechanistic terms. Pharmacotherapy for DU is limited, comprising primarily parasympathomimetic agents, which have questionable efficacy and adverse side effects. More effective and tolerable treatment options to restore bladder contractility would represent a major therapeutic advance for patients suffering from DU. However, the goal of successful pharmacologic treatment of DU will only be realized by understanding mechanisms regulating bladder SM contraction and their dysregulation in DU. We recently identified the detrusor smooth muscle as a major site of expression of neuropilin 2 (Nrp2). Exposure of bladder smooth muscle cells to the neuropilin 2 ligand semaphorin 3F (SEMA3F) evoked profound cytoskeletal changes, accompanied by inhibition of RhoA, decreased myosin light chain phosphorylation, and reduced cytoskeletal stiffness. Consistent with this, forced expression of SEMA3F via adenoviral transduction in vivo led to reduced bladder SM contractility. Conversely, knockout of either Nrp2 or Sema3F in vivo enhanced bladder SM contractility compared to non-deleted controls. New data show that in bladders undergoing decompensation following partial bladder outlet obstruction (pBOO), Nrp2 deletion restored SM contractility compared to non-deleted controls. Lastly, new analysis of human bladder specimens revealed an inverse correlation between detrusor contractility and NRP2 expression. Based on these observations, we hypothesize that the SEMA3F-neuropilin 2 network inhibits bladder SM contractility in vivo and that targeting this axis restores contractile function under conditions of DU. The hypothesis will be tested with the following Specific Aims: (1) Determine the mechanisms underlying Sema3F- Nrp2-mediated inhibition of bladder SM contractility. (2) Determine the functional consequences of targeting the Sema3F-Nrp2 axis in a model of pBOO. We will employ novel mouse models of Nrp2- and Sema3F- deficiency, tension testing in muscle strips, biochemical and histological analyses, cystometric evaluation and a physiologically relevant mouse model of bladder outlet obstruction to achieve our objectives. At the end of the project period we expect to have determined the mechanism(s) whereby the Sema3F-Nrp2 axis inhibits smooth muscle contractility, the consequences of Sema3F and Nrp2 perturbation for bladder pathophysiology and how the Sema3F-Nrp2 network may be exploited therapeutically to restore contractility in DU.