Therapy for Obesity-associated Stress Urinary Incontinence

 描述(申请人提供)：超重的女性容易出现肥胖相关的压力性尿失禁(OA-SUI)，但由于其发病机制尚未很好地阐明，因此尚未开发出针对该疾病的特定治疗方法。由于肥胖者常发生骨骼肌萎缩，因此可能与尿路横纹肌功能障碍有关。激活内源性干细胞/祖细胞以再生受损的肌肉可能是一种有用的治疗方法。然而，全身应用干细胞或其激活剂可能会对非靶标器官或组织造成危险的副作用。局部给药不能解决这个问题，因为注射的干细胞或祖细胞经常迁移到靶区之外。我们的实验室在过去的12年里一直专注于内源性干细胞/祖细胞的生物学研究，正在开发一种非侵入性的方法，可以在选定的位置招募和保留这些细胞，或者在原位激活它们。我们的初步实验表明，低能量冲击波(LESW)可以激活尿路肌祖细胞；它们还可以下调肌肉生长抑制素。我们假设，通过激活驻留干细胞生长新的肌纤维，LESW可以逆转OA-SUI。为了阐明机制和确定潜在的临床方法，我们还在研究一种新的DNA抑制方法--“簇状规则间隔短回文重复干扰”(CRISPRi)对肌肉生长抑制素的抑制作用。我们将使用啮齿类动物的OA-SUI模型来评估CRISPRi和/或LESW治疗的结构和功能结果，并将结果与减肥(临床上通常采用的治疗方法)的效果进行比较。为了阐明肥胖如何影响女性尿道括约肌的结构和功能，激活其驻留干细胞的分子机制，以及LESW对其激活的影响。我们还将建立诱导肌肉再生的可行性。 通过抑制肌肉生长抑制素信号。这些目标导致我们提出以下具体目标：1.验证一种可用于研究肥胖引起的尿道纹肌肉改变的动物模型。2.比较LESW组与减肥组在结构和功能上的改善。3.抑制肌肉生长抑素促进OA-SUI大鼠括约肌功能恢复。4.探讨高脂血症和高血糖对干细胞存活、分化和转录信号的影响，以及LESW对其的影响。

 DESCRIPTION (provided by applicant): Overweight females are prone to obesity-associated stress urinary incontinence (OA-SUI), but because the mechanisms underlying its pathology have not been well elucidated, no specific therapies for the condition have been developed. It is possible that dysfunction of urethral striated muscle contributes to OA-SUI, as atrophy of skeletal muscle often occurs in obese people. Activating endogenous stem/progenitor cells to regenerate damaged muscle could comprise a useful therapeutic approach. However, systemic administration of stem cells or their activators can cause dangerous side effects in off-target organs or tissues. Localized administration of curatives does not resolve this problem, because injected stem or progenitor cells often migrate outside the target area. Our laboratory, which has focused on the biology of endogenous stem/progenitor cells for the past 12 years, is developing a non-invasive method that can recruit and retain these cells at selected sites, or activate them in situ. Our pilot experiments demonstrate that low-energy shock waves (LESW) activates urethral muscle progenitor cells; they also down-regulate the muscle growth inhibitor myostatin. We hypothesize that by activating resident stem cells to grow new myofibers, LESW can reverse OA-SUI. To clarify mechanisms and identify potential clinical approaches, we are also investigating myostatin inhibition via a novel DNA-inhibiting method called "clustered regularly interspaced short palindromic repeats interference" (CRISPRi). We will use a rodent OA-SUI model to assess structural and functional outcomes of treatment with CRISPRi, LESW, or both, and compare the results with the effects of weight-loss (the usual treatment taken in the clinic). To elucidate how obesity affects the structure and function of the female urethral sphincter, the molecular mechanisms involved in activating its resident stem cells, and the impacts LESW has on their activation. We will also establish the feasibility of inducing regeneration of this muscle by inhibiting myostatin signaling. These objectives lead us to propose the following Specific Aims: 1. To validate an animal model useful for the study of obesity-induced alterations of urethral striated muscle. 2. To measure the structural and functional improvements in OA-SUI sphincter dysfunctions afforded by LESW compared with weight loss. 3. To increase sphincter recovery by myostatin inhibition in rats with OA-SUI. 4. To identify the effects of dyslipidemia and hyperglycemia on the survival, differentiation, and transcriptional signatures of stem cells through the modulation of myostatin signaling, and its counteraction by LESW.