Novel Studies of Bladder Regeneration in a Rodent Model

描述(申请人提供)：本申请针对数百万患有膀胱疾病/功能障碍的患者，这些患者与先天性畸形、癌症、感染、炎症或中枢或外周神经系统损伤有关。无论病因如何，在所有情况下，这些情况最终都会对膀胱组织结构或功能造成很大程度上不可修复的损害，最终影响膀胱的充盈、储存或排空能力。随之而来的膀胱功能障碍显著降低了患者的生活质量，还可能由于肾脏的上游影响而导致显著的发病率。组织工程和再生医学技术代表了一种潜在的解决方案，可以解决与这些疾病相关的可存活膀胱组织不足的问题。虽然最近报道了这些技术在患有先天性脊髓损伤(即脊髓脊膜膨出)的年轻患者中首次临床成功，但如果人们希望将这些技术扩展到更大的潜在患者群体尚未满足的医疗需求，那么毫无疑问，治疗方面仍有改进的空间。由于啮齿动物和人类的膀胱再生有几个共同的特征，我们提出了在啮齿动物模型上进行膀胱大部切除后膀胱再生的新研究。其基本原理是，改进对体内正常膀胱再生过程的机械理解将是进一步临床进展的绝对先决条件。为此，我们将：具体目标#1：使用显微CT和MRI成像技术和有意识的膀胱测量方法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方法评估体外宿主组织再生反应的进展。具体目标#3：描述膀胱再生反应的细胞基础和组织学特征。高分辨率成像技术与体内膀胱功能、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非侵入性标志物。这种方法的力量来自于将再生的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来最大限度地发挥身体在体内实现增强/最大组织形成的潜力。 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会对膀胱组织造成不可逆转的损害，从而导致永久性的膀胱功能损害。这种衰弱的损伤影响着数以百万计的美国人，并导致生活质量低下。我们建议在一个临床相关的啮齿动物模型中研究膀胱再生的过程，以便更好地应用组织工程和再生医学技术来创造来自患者自身细胞的新的功能组织。

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.