Phenotyping Interstitial Cystitis/Bladder Pain Syndrome by ICE-MRI Based Bladder Permeability Assay

间质性膀胱炎/膀胱痛综合征(IC/BPS)是一种慢性、衰弱的疾病，影响超过2 在美国境内有数百万人。近日，ICS慢性盆腔疼痛工作组已将 IC/BPS进入任何一种过敏性膀胱，没有解释IC/BPS症状的可识别的病理， 膀胱镜检查有Hunner病变的IC/BPS(HIC)或无病变的IC/BPS(NHIC)。虽然从病因学的角度来看 IC/BPS是多因素的，大量证据支持膀胱粘膜通透性受损，如 是HIC的主要病理生理原因。然而，在真正的识别中仍然存在变异性(5%-57%) 以膀胱镜检查为基础的以膀胱为中心的IC/BPS。因此，一种微创、可靠的检测方法 在不引起疼痛或向受试者暴露电离辐射的情况下测量膀胱通透性可能能够 符合FDA规定的诊断测试标准。在过去的资金支持下，我们开发了一种辐射 自由，微创测定膀胱粘膜通透性，我们证明了 膀胱内对比增强磁共振成像(ICE-MRI)测量小鼠膀胱通透性的研究 7T和9.4T高场扫描大鼠膀胱(PMC7509285；PMC6028942；PMC8484474)。一把钥匙 我们的ICE-MRI测定膀胱通透性的特点是经尿路导管注入加多布曲尔和 阿魏催产素混合液和MRI利用的是滴注浓度之间的线性关系 加多布曲尔被动进入粘膜引起T1松弛速率的浓度依赖性变化 (1/T1松弛时间)。当加多布曲尔注入膀胱腔时，向下扩散到粘膜 浓度梯度，我们的初步数据表明，粘膜损伤加速了加多布曲尔的作用 相对于正常区域的扩散。我们现在寻求资金支持，以产生临床证据 ICE-MRI可作为IC/BPS患者以膀胱为中心的表型的诊断试验 补充传统的基于膀胱镜的诊断。遵循特定的目标将检验这样的假设 Gadobutrol合剂对HIC和NHIC膀胱粘膜通透性的定量影响 无症状对照受试者：目标1：校准基于ICE-MRI的膀胱粘膜通透性测定 HIC、NHIC患者和膀胱镜检查正常的无症状受试者。在横截面上 10例经膀胱镜检查的HIC患者、10例NHIC患者和10例无症状患者的前瞻性研究 作为对照，我们将校准基于ICE-MRI的膀胱粘膜通透性测定。目标2：制造 无菌临床试验材料和完成基于ICE-MRI的膀胱渗透性的IND/IDE提交 化验试剂盒。一种无辐射、客观的膀胱通透性诊断试验可以客观地分型IC/BPS IC/BPS是以膀胱为中心的，从而识别最有可能从抗-TRAN中受益的患者 炎症治疗，避免延误获得适当的医疗护理。我们的化验还可以使 目的选择IC/BPS患者进行针对膀胱病理的新的治疗方法的临床试验。

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic, debilitating condition that affects more than 2 million individuals within the US. Recently, the chronic pelvic pain working group of the ICS has classified IC/BPS into either hypersensitive bladder with no identifiable pathology explaining the symptoms of IC/BPS, IC/BPS with Hunner lesion (HIC) or IC/BPS with no lesions on cystoscopy (NHIC). Though the etiology of IC/BPS is multifactorial, a large body of evidence supports the impairment of bladder mucosal permeability as a major pathophysiological cause in HIC. Yet, there remains variability (5-57%) in the true identification of IC/BPS that is bladder-centric on the basis on cystoscopy. Therefore, a minimally invasive, assay that reliably measures bladder permeability without evoking pain or exposing ionizing radiation to subjects may be able to meet the FDA regulatory criteria for a diagnostic test. With the past funding support, we developed a radiation free, minimally invasive assay of bladder mucosal permeability, and we demonstrated the validity of intravesical contrast enhanced magnetic resonance imaging (ICE-MRI) to measure permeability of thin mouse and rat bladder at high field scanners of 7T and 9.4T (PMC7509285; PMC6028942; PMC8484474). A key feature of our ICE-MRI assay of bladder permeability is the transurethral catheter instillation of Gadobutrol and Ferumoxytol mixture and then MRI capitalizes on the linear relationship between the concentration of instilled Gadobutrol diffusing passively into the mucosa to cause concentration dependent changes in T1 relaxation rate (1/T1 relaxation time) of the mucosa. While Gadobutrol instilled into bladder lumen diffuses into mucosa down the concentration gradient, our preliminary data demonstrates that mucosa lesion accelerates the Gadobutrol diffusion relative to normal areas. We now seek funding support to generate clinical evidence for demonstrating that ICE-MRI can be a diagnostic test for bladder-centric phenotype in IC/BPS patients to complement conventional cystoscopy-based diagnosis. Following Specific Aims will test the hypothesis that bladder mucosal permeability of instilled Gadobutrol mixture descends quantitatively from HIC >NHIC >asymptomatic control subjects.: Aim 1: To calibrate the ICE-MRI based bladder mucosal permeability assay on HIC, NHIC patients and asymptomatic subjects who have normal cystoscopic findings. In a cross-sectional prospective study on previously cystoscoped 10 HIC patients, 10 NHIC patients, and 10 asymptomatic controls, we will calibrate the ICE-MRI based bladder mucosal permeability assay. Aim 2: To manufacture sterile clinical trial materials and complete the IND/IDE submission for the ICE-MRI based bladder permeability assay kit. A radiation-free, objective diagnostic test of bladder permeability can objectively phenotype IC/BPS IC/BPS that is bladder-centric, thereby identifying patients who would be most likely to benefit from anti- inflammatory therapies and avoid the delay in getting appropriate medical care. Our assay can also enable the objective selection of IC/BPS patients for clinical trials of newer therapies targeting bladder pathology.