Novel Studies of Bladder Regeneration in a Rodent Model

描述（由申请人提供）：此应用程序针对数百万患有先天性异常，癌症，感染，炎症或中枢或周围神经系统病变相关的膀胱疾病/功能障碍的患者。无论病因如何，在所有情况下，这些疾病最终都会对膀胱组织结构或功能造成很大程度上无法修复的损害，最终影响膀胱填充、储存或排空的能力。随之而来的膀胱功能障碍大大降低了患者的生活质量，并且由于对肾脏的上游影响，也可能导致显著的发病率。组织工程和再生医学技术代表了与这些条件相关的可存活膀胱组织缺陷的潜在解决方案。虽然这些技术在先天性脊髓病变（即脊髓脊膜膨出）的年轻患者中取得了首次临床成功，但毫无疑问，如果希望将这些技术扩展到更多潜在患者群体的未满足医疗需求，则治疗还有改进的空间。由于啮齿动物和人类的膀胱再生有几个共同的特征，我们提出在啮齿动物模型中进行次全膀胱切除术后膀胱再生的新研究。其基本原理是，提高对体内正常膀胱再生过程的机制理解将是进一步临床进展的绝对先决条件。具体目标1：利用微CT和MRI成像技术以及有意识的膀胱测量来评估体内宿主组织再生的进展。具体目标#2：使用药理学和生理学分析评估体外宿主组织再生反应的进展。具体目标#3：表征膀胱再生反应的细胞基础和组织学特征。高分辨率成像方式与体内膀胱功能、体外组织功能和组织学的直接测量相结合，将建立膀胱再生的基线特征，以及与正常膀胱再生相关的生理里程碑的无创标记。这种方法的力量源于将再生膀胱与同一动物的天然膀胱进行比较。最重要的目标是利用获得的新见解，最大限度地提高身体在体内实现增强/最大组织形成的潜力。

DESCRIPTION (provided by applicant): This application targets the millions of patients suffering from bladder disease/dysfunction related to congenital anomalies, cancer, infection, inflammation or lesions of the central or peripheral nervous system. Regardless of etiology, in all cases these conditions eventually result in largely irreparable damage to bladder tissue structure or function, ultimately affecting the ability of the bladder to fill, store or empty. The ensuing bladder dysfunction significantly reduces the patient's quality of life, and can also lead to significant morbidity due to upstream effects on the kidneys. Tissue engineering and regenerative medicine technologies represent a potential solution to the deficit of viable bladder tissue associated with these conditions. While the first clinical success of these techniques have recently been reported in young patients with congenital spinal cord lesions (i.e., myelomeningocele), there is no doubt that there is room for therapeutic improvement if one wishes to extend these technologies to the unmet medical needs of the much larger potential patient population. Because bladder regeneration in rodents and man shares several common features, we propose novel studies of bladder regeneration following subtotal cystectomy in a rodent model. The rationale is that improved mechanistic understanding of the normal bladder regeneration process in vivo would be an absolute prerequisite to further clinical progress. To this end we shall: Specific Aim #1: Assess progression of host tissue regeneration in vivo using micro CT and MRI imaging techniques and conscious cystometry measures. Specific Aim #2: Assess the progression of the host tissue regeneration response in vitro using pharmacological and physiological assays. Specific Aim #3: Characterize the cellular basis and histological features of the regenerative response of the urinary bladder. The combination of high resolution imaging modalities with direct measures of bladder function in vivo and tissue function and histology in vitro will establish the baseline characteristics of bladder regeneration as well as noninvasive markers for physiological milestones associated with normal bladder regeneration. The power of this approach stems from comparison of the regenerated bladder with the native bladder from the same animal. The over-ridding goal is to leverage the novel insights obtained to maximize the body's potential for achieving enhanced/maximal tissue formation in vivo. PUBLIC HEALTH RELEVANCE Cancer, congenital deformities, infection, inflammation, traumatic injury and nerve lesions produce irreversible damage to bladder tissue resulting in a permanent impairment in bladder function. Such debilitating impairments affect millions of Americans and lead to a poor quality of life. We propose to study the process of bladder regeneration in a clinically relevant rodent model in order to better apply tissue engineering and regenerative medicine technologies to the creation of new functional tissue derived from the patients own cells.