Pathophysiology of Anorectal Disorders

描述（由申请人提供）：本研究计划的目标是通过使用多学科创新方法阐明这种疾病的风险因素和机制，加强预防和改善女性大便失禁（FI）的管理。虽然目前的概念强调肛门括约肌无力的作用，我们的流行病学和机制研究强烈支持这一假设，即FI是由复杂的直肠肛门感觉运动功能障碍，而不是孤立的肛门功能障碍。我们的具体目标是评估以下假设：（i）子宫切除术后的女性和急迫性FI女性的直肠更僵硬;（iia）主要由于神经源性而非肌源性机制导致的部分可逆性直肠运动功能障碍导致急迫性FI女性的直肠超敏反应;（iib）去神经超敏反应导致子宫切除术后直肠僵硬度增加;可乐定可恢复直肠感觉运动功能，从而改善FI的症状。我们相应的目的是（i）在24名无症状女性和24名患有急性FI的女性中，在直肠球囊扩张期间通过同时MRI测量整体和区域直肠应力：应变关系，同时控制子宫切除术;（iia）比较阿托品和硝苯地平对直肠机械特性的急性影响（即，顺应性，容量，和阶段性反应膨胀）和直肠的感觉膨胀在56名妇女和36名妇女没有迫切FI，也控制子宫切除术;（iib）评估的影响，胆碱能激动剂对直肠感觉运动在24名妇女有或没有子宫切除术;和（iii）在40名患有FI的妇女的双盲安慰剂对照研究中研究可乐定对症状和直肠感觉运动功能的影响。通过测试与新疗法相结合的机制假设，这些研究有望从根本上改变我们对女性FI的理解和管理。 公共卫生相关性：大便失禁（FI）影响10%的绝经后妇女，高达20%。FI会造成严重的痛苦，损害日常功能，并有助于机构化。FI的病理生理机制知之甚少，而可用的治疗选择是有限的，没有证据为基础的，主要集中在改善肛门括约肌功能。这一建议将加强我们对机制的理解，并评估管理FI的新方法。

DESCRIPTION (provided by applicant): The goals of this research program are to enhance the prevention and improve the management of fecal incontinence (FI) in women by clarifying the risk factors and mechanisms for this disorder using multidisciplinary, innovative approaches. While current concepts emphasize the role of anal sphincter weakness, our epidemiological and mechanistic studies strongly support the hypothesis that FI is caused by complex of recto-anal sensorimotor dysfunctions rather than isolated anal dysfunction. Our specific aims are to assess the hypotheses that: (i) The rectum is stiffer in women who have had a hysterectomy and also in women with urge FI; (iia) Partially reversible rectal motor dysfunctions predominantly due to neurogenic rather than myogenic mechanisms contribute to rectal hypersensitivity in women with urge FI; (iib) denervation supersensitivity contributes to increased rectal stiffness after a hysterectomy; and (iii) clonidine will restore rectal sensorimotor functions and thereby improve symptoms in FI. Our corresponding aims are to (i) measure overall and regional rectal stress:strain relationships by simultaneous MRI during rectal balloon distention in 24 asymptomatic women and in 24 women with urge FI, also controlling for hysterectomy; (iia) compare the acute effects of atropine and nifedipine on rectal mechanical properties (i.e., compliance, capacity, and the phasic response to distention) and rectal perception of distention in 56 women with and 36 women without urge FI, also controlling for hysterectomy; (iib) assess the effects of a cholinergic agonist on rectal sensorimotor in 24 women who have or have not had a hysterectomy; and (iii) study the effects of clonidine on symptoms and rectal sensorimotor functions in a double- blind placebo-controlled study of 40 women with FI. By testing mechanistic hypotheses which are integrated with a new therapy, these studies are poised to fundamentally alter our understanding and management of FI in women. Public Health Relevance: Fecal incontinence (FI) affects 10% of all and up to 20% of postmenopausal women. FI can cause significant distress, impair daily functioning, and contribute to institutionalization. The pathophysiology of FI is poorly understood, while available therapeutic options are limited, not evidence-based, and primarily focus on improving anal sphincter function. This proposal will enhance our understanding of the mechanisms and assess novel approaches to manage FI.