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。我们发现，由于肥胖者常发生骨骼肌萎缩，所以尿道部和盆底横纹肌功能障碍与骨性骨质疏松症的发病有关。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在非靶标器官或组织中引起不良副作用。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13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，在非常特定的能量水平上的低能量冲击波(LESW)可以激活尿路和盆底的肌祖细胞；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，并将结果与减肥的效果(临床采用的一线治疗)进行比较。为了阐明肥胖如何影响女性尿道括约肌和盆底肌的结构和功能，激活其驻留干细胞的分子机制，以及LESW对其激活和分化的影响。我们还将确定通过抑制肌肉抑制素信号来诱导肌肉再生的可行性。这些目标使我们提出了以下具体目标：1.观察LESW对肥胖相关的大鼠尿道和盆底横纹肌功能障碍的影响；2.通过抑制肌肉生长抑素促进OA-SUI大鼠的尿道括约肌和盆底肌肉的恢复。3.通过对肌肉生长抑制素信号转导通路的调控，明确血脂异常和高血糖对肌源性干细胞的影响，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. We have identified that dysfunction of urethral and pelvic floor striated muscles contributes to OA-SUI, as atrophy of skeletal muscle often occurs in obese people. Activating endogenous stem/progenitor cells to regenerate damaged muscles could comprise a useful therapeutic approach. However, systemic administration of stem cells or their activators can cause undesirable 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 13 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) at a very specific energy level activates urethral and pelvic floor 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 first line treatment taken in the clinic). To elucidate how obesity affects the structure and function of the female urethral sphincter and pelvic floor muscles, the molecular mechanisms involved in activating its resident stem cells, and the impacts LESW has on their activation and differentiation. 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 examine the effect of LESW and weight loss in a rat model of obesity-associated urethral and pelvic floor striated muscle dysfunction 2.To enhance the recovery of urethral sphincter and pelvic floor muscle by myostatin inhibition in rats with OA-SUI. 3. To identify the effects of dyslipidemia and hyperglycemia on muscle derived stem cells (MDSC) through the modulation of myostatin signaling, and its counteraction by LESW.