Novel Studies of Bladder Regeneration in a Rodent Model

描述（由申请人提供）：本申请针对数百万患有与先天性异常、癌症、感染、炎症或中枢或外周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，这些病症最终导致对膀胱组织结构或功能的大部分不可修复的损伤，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显著降低患者的生活质量，并且由于对肾脏的上游影响，还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行膀胱组织缺陷的潜在解决方案。虽然最近在患有先天性脊髓病变的年轻患者中报道了这些技术的第一次临床成功（即，脊髓脊膜膨出），毫无疑问，如果希望将这些技术扩展到更大的潜在患者群体的未满足的医疗需求，则存在治疗改进的空间。由于啮齿类动物和人类的膀胱再生有几个共同的特点，我们提出了新的研究膀胱再生后，在啮齿类动物模型的次全膀胱切除术。其基本原理是，改善机制的理解正常膀胱再生过程中，体内将是一个绝对的先决条件，以进一步的临床进展。为此，我们将：具体目标1：使用显微CT和MRI成像技术和有意识膀胱测压测量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试验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。高分辨率成像模式与体内膀胱功能和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非侵入性标志物。这种方法的力量源于再生膀胱与来自同一动物的天然膀胱的比较。最重要的目标是利用获得的新见解来最大化身体的潜力，以实现增强/最大的体内组织形成。 公共卫生相关性 癌症、先天性畸形、感染、炎症、创伤性损伤和神经损伤对膀胱组织产生不可逆的损伤，导致膀胱功能的永久性损伤。这种使人衰弱的损伤影响了数百万美国人，并导致生活质量低下。我们建议在临床相关的啮齿动物模型中研究膀胱再生的过程，以便更好地将组织工程和再生医学技术应用于从患者自身细胞中产生新的功能组织。

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.