Psychosocial Stress Effects on Regenerative Medicine Therapies for Lower Urinary Tract Disorders in Nonhuman Primates

这项建议是对PAS-19-241的回应，刺激了泌尿外科跨学科团队 机会研究，其目的是促进创新，高质量， 与NIDDK相关的跨学科研究。重要的是，这个通行证和一个前科 工作坊确认尿失禁女性的心理社会因素是一个重要的 知识鸿沟。为此，我们汇集了来自行为科学、泌尿学、分子生物学等领域的专家 病理学和再生医学，以进一步探索我们的初步发现 处于社会地位的雌性猴子对尿失禁的细胞治疗反应不佳 作为他们占主导地位的对手。我们现在提出一个更全面的方法来评估(A) 交感神经系统(SNS)觉醒，下丘脑-垂体-肾上腺(HPA)激活，以及 群居猴子卵巢功能受损；和(B)可能的途径 哪种社会从属压力会影响内部的结构和功能再生 尿路括约肌。社会从属压力可能通过两条途径 调节这些过程的是皮质醇和SNS对组织和细胞的破坏性炎症和 雌激素缺乏相关的细胞动员抑制。这些过程不是相互的 排他性，可能涉及CXCL12/CXCR4信号通路。基于我们之前的 研究和出版的文献中，我们的中心假设是心理社会压力 通过减少组织的动员来抑制细胞治疗的再生效果 修复骨髓祖细胞，增加造血组织的存在 破坏尿括约肌中的炎性细胞。这一假设将在一个 使用我们特征良好的雌性进行的前瞻性、随机、非人类灵长类动物临床前试验 食蟹猴因社会从属而产生的心理社会压力模型，以及我们的 先天性尿括约肌缺乏症。我们的具体目标是确定 社会地位：1)结构(细胞、非细胞、血管、神经)和 女性自体skMPC治疗对功能(尿括约肌和膀胱)的影响 2)注射Lenti-M-Cherry+skMPC细胞滞留，并标记Lenti GFP+ 主从猴的尿括约肌骨髓细胞动员；3) 社会从属压力对炎症性细胞因子丰度和极化的影响 尿括约肌中的细胞和相关分子；以及4)社会地位 对细胞治疗诱导的组织再生的影响是由行为应激、SNS、 HPA，或卵巢功能。这项翻译研究的结果将促进理解 女性泌尿系疾病的局限性和未来可能的再生医学策略 大小便失禁。

This proposal is a response to PAS-19-241, Stimulating Urology Interdisciplinary Team Opportunity Research, the aim of which is to promote innovative, high-quality, interdisciplinary research relevant to the NIDDK. Importantly, this PAS and a prior workshop identified psychosocial factors in women with urinary incontinence as an important knowledge gap. To this end, we bring together experts from behavioral sciences, urology, molecular pathology, and regenerative medicine to explore further our initial findings that socially subordinate female monkeys do not respond as well to cell therapy for urinary incontinence as their dominant counterparts. We now propose a more comprehensive approach to assess (a) sympathetic nervous system (SNS) arousal, hypothalamic-pituitary-adrenal (HPA) activation, and impaired ovarian function in socially housed monkeys; and (b) the likely pathways by which social subordination stress affects structural and functional regeneration within the urinary sphincter. Two likely pathways through which social subordination stress may modulate these processes are cortisol and SNS effects on tissue and cell damaging inflammation and estrogen-deficiency-associated inhibition of cell mobilization. These processes are not mutually exclusive and may involve the CXCL12/CXCR4 signaling pathway. Based on our previous studies and the published literature, our central hypothesis is that psychosocial stress inhibits the regenerative effects of cell therapy by reducing the mobilization of tissue healing bone marrow progenitor cells, and increasing the presence of hematopoietic tissue damaging inflammatory cells in the urinary sphincter. This hypothesis will be tested in a prospective, randomized, nonhuman primate preclinical trial using our well-characterized female cynomolgus monkey model of psychosocial stress due to social subordination, and our model of intrinsic urinary sphincter deficiency. Our Specific Aims are to determine the effect of social status on: 1) the structural (cellular, acellular, vascular, innervation) and functional (urinary sphincter and bladder) effects of autologous skMPC therapy in female primates with ISD; 2) The injected lenti-M-cherry+ skMPC cell retention in, and lenti GFP+ labeled bone marrow cell mobilization to, the urinary sphincter of dominant and subordinate monkeys; 3) The effect of social subordination stress on abundance and polarization of inflammatory cells and associated molecules in the urinary sphincter; and 4) Whether social status effects on cell therapy-induced tissue regeneration are mediated by behavioral stress, SNS, HPA, or ovarian function. The results of this translational research will promote understanding of limitations and potential future regenerative medicine strategies for women with urinary incontinence.