Therapy for Obesity-associated Stress Urinary Incontinence

 描述（由申请人提供）：超重女性容易发生肥胖相关的压力性尿失禁（OA-SUI），但由于其病理学机制尚未得到很好的阐明，因此尚未开发出针对该病症的特异性治疗方法。我们已经确定尿道和骨盆底横纹肌功能障碍有助于OA-SUI，因为骨骼肌萎缩通常发生在肥胖人群中。激活内源性干细胞/祖细胞以再生受损的肌肉可以包括有用的治疗方法。然而，干细胞或其活化剂的全身施用可在脱靶器官或组织中引起不期望的副作用。局部施用治疗剂不能解决这个问题，因为注射的干细胞或祖细胞经常迁移到靶区域之外。我们的实验室在过去的13年里一直专注于内源性干/祖细胞的生物学，正在开发一种非侵入性方法，可以在选定的部位招募和保留这些细胞，或原位激活它们。我们的试点实验表明，低能量冲击波（LESW）在一个非常特定的能量水平激活尿道和盆底肌肉祖细胞;他们也下调肌肉生长抑制剂肌肉生长抑制素。我们假设通过激活常驻干细胞生长新的肌纤维，LESW可以逆转OA-SUI。为了阐明机制并确定潜在的临床方法，我们还通过一种称为“成簇规则间隔短回文重复干扰”（CRISPRi）的新型DNA抑制方法研究肌生长抑制素抑制。我们将使用啮齿动物OA-SUI模型来评估CRISPRi、LESW或两者治疗的结构和功能结果，并将结果与减肥（临床一线治疗）的效果进行比较。阐明肥胖如何影响女性尿道括约肌和骨盆底肌肉的结构和功能，激活其常驻干细胞的分子机制，以及LESW对其激活和分化的影响。我们还将建立通过抑制肌肉生长抑制素信号诱导这种肌肉再生的可行性。这些目的使我们提出以下具体目的：1.在肥胖相关的尿道和盆底横纹肌功能障碍的大鼠模型中检查LESW和体重减轻的效果2.通过抑制OA-SUI大鼠的肌肉生长抑制素来促进尿道括约肌和盆底肌的恢复。3.研究血脂异常和高血糖对肌源性干细胞（MDSC）的影响，以及LESW对肌生长抑制素信号转导的抑制作用。

 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.