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

心理社会压力对非人类灵长类下尿路疾病再生医学治疗的影响

• 批准号: 10375461
• 负责人: Carol A. Shively
• 金额: $ 67.61万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375461
• 关键词: 3-Dimensional; Abdomen; Adrenal Glands; Affect; Anti-Inflammatory Agents; Apoptosis; Arousal; Autologous; Behavioral; Behavioral Sciences; Bladder; Blood Circulation; Blood Vessels; Bone Marrow; Bone Marrow Cells; CXCL12 gene; CXCR4 Signaling Pathway; Cell Proliferation; Cell Therapy; Cells; Characteristics; Cherry - dietary; Clinical Research; Collagen; Data; Dexamethasone; Educational workshop; Elastin; Estrogens; Exhibits; Female; Fiber; Fibrosis; Functional Regeneration; Future; Gene Expression Profile; Goals; Hydrocortisone; Hypothalamic structure; Hypoxia; Image; Impairment; Inflammation; Inflammatory; Interdisciplinary Study; Knowledge; Label; Literature; Lower urinary tract; Lymphocyte; Macaca fascicularis; Measures; Mediating; Modeling; Monkeys; Muscle; Myoblasts; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Nerve; Ovarian; Pathway interactions; Pattern; Phenotype; Physiological; Pituitary Gland; Primates; Process; Psychological Stress; Psychosocial Factor; Psychosocial Stress; Publishing; Randomized; Regenerative Medicine; Reporting; Research; Rest; Signal Pathway; Skeletal Muscle; Social status; Sphincter; Stress; Stress Urinary Incontinence; Sympathetic Nervous System; Testing; Tissues; Translational Research; Translations; Urethra; Urinary Incontinence; Urologic Diseases; Urology; Vascularization; Whole Blood; Woman; base; bone healing; cell injury; chemokine; design; experience; hematopoietic tissue; innovation; macrophage; molecular pathology; monocyte; multidisciplinary; nerve supply; nonhuman primate; ovarian dysfunction; pre-clinical; preclinical study; preclinical trial; pressure; prospective; regenerative; regenerative treatment; response; senescence; small social group; social; stem cells; tissue regeneration; tissue repair; urinary; vascular inflammation

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.

该提案是对 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 和之前的 研讨会确定女性尿失禁的心理社会因素是一个重要的因素 知识差距。为此，我们汇集了来自行为科学、泌尿学、分子科学的专家 病理学和再生医学进一步探索我们的初步发现 社会地位较低的雌性猴子对尿失禁的细胞疗法反应不佳 作为他们的主要对手。我们现在提出一种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 社会饲养的猴子卵巢功能受损； (b) 可能的途径 社会从属压力会影响结构和功能的再生 尿道括约肌。社会从属压力可能通过两种途径产生 调节这些过程的是皮质醇和 SNS 对组织和细胞损伤性炎症的影响， 雌激素缺乏相关的细胞动员抑制。这些过程不是相互的 独有的，可能涉及 CXCL12/CXCR4 信号通路。根据我们之前的 研究和已发表的文献中，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 治愈骨髓祖细胞，并增加造血组织的存在 破坏尿道括约肌中的炎症细胞。该假设将在 使用我们特征明确的女性进行前瞻性、随机、非人类灵长类动物临床前试验 由于社会从属而导致的心理社会压力的食蟹猴模型，以及我们的模型 尿道内括约肌缺陷。我们的具体目标是确定以下效果： 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 患有 ISD 的灵长类动物； 2) 将注射的lenti-M-cherry+ skMPC细胞保留在其中，并用lenti GFP+标记 骨髓细胞动员至优势猴和从属猴的尿道括约肌； 3) 的 社会从属压力对炎症丰度和极化的影响 尿道括约肌中的细胞和相关分子； 4) 是否有社会地位 对细胞治疗诱导的组织再生的影响是由行为压力、SNS、 HPA，或卵巢功能。这项转化研究的结果将促进理解 泌尿系女性的局限性和未来潜在的再生医学策略 失禁。