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

本提案是对PAS-19-241，刺激泌尿科跨学科团队的回应 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PAS和一个先前的 研讨会确定了心理社会因素在妇女尿失禁的重要 知识差距。为此，我们汇集了来自行为科学，泌尿学，分子生物学， 病理学和再生医学来进一步探索我们的初步发现， 社会地位低下的雌性猴子对尿失禁的细胞疗法没有反应 作为他们的主要对手。我们现建议采用一个更全面的方法来评估（a） 交感神经系统（SNS）唤醒，下丘脑-垂体-肾上腺（HPA）激活，以及 社会圈养的猴子中卵巢功能受损;和（B）可能的途径， 社会从属压力会影响内部的结构和功能再生， 尿道括约肌社会从属压力可能通过两种途径 调节这些过程的是皮质醇和SNS对组织和细胞损伤炎症的影响， 雌激素缺乏相关的细胞动员抑制。这些过程不是相互的。 它是排他性的，可能涉及CXCL 12/CXCR 4信号通路。基于我们之前 研究和出版的文献，我们的中心假设是，心理社会压力， 通过减少组织动员来抑制细胞治疗的再生效果 愈合骨髓祖细胞，并增加造血组织的存在 破坏尿道括约肌的炎症细胞这一假设将在一个 一项前瞻性、随机、非人灵长类动物临床前试验，使用我们的特征良好的雌性 食蟹猴模型的社会心理压力，由于社会从属地位，和我们的模型， 先天性尿道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，神经支配）和 自体skMPC治疗对女性功能（尿道括约肌和膀胱）的影响 2）注射的lenti-M-cherry+ skMPC细胞保留，并且lenti GFP+标记的 骨髓细胞动员，占主导地位的和从属猴的尿道括约肌; 3） 社会从属压力对炎症因子丰度和极化影响 尿道括约肌中的细胞和相关分子;以及4）是否社会地位 对细胞疗法诱导的组织再生的作用是由行为应激，SNS， HPA或卵巢功能。这一转化研究的结果将促进理解 的局限性和潜在的未来再生医学战略的妇女泌尿 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.