Autonomic regulation of lacrimal stem cells

泪腺干细胞的自主调节

• 批准号: 9387922
• 负责人: Sarah Monica Knox
• 金额: $ 42.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387922
• 关键词: Ablation; Acinar Cell; Acinus organ component; Address; Adult; Affect; Aging; Architecture; Autoimmune Diseases; Autologous; Autologous Transplantation; BMI1 gene; Behavior; Behavioral Mechanisms; Biochemical; Biological Assay; CXCR4 gene; Cell Differentiation process; Cell Maintenance; Cell Transplants; Cells; Clinical; Data; Development; Disease; Dry Eye Syndromes; Duct (organ) structure; Epithelial; Epithelium; Event; Eye diseases; Functional disorder; Gene Targeting; Genetic; Genetic Transcription; Goals; Homeostasis; Human; Impairment; Inflammation; Injury; Lacrimal gland structure; Maintenance; Mediating; Morphogenesis; Mus; Natural regeneration; Nerve; Neuropeptide Y Receptor; Operative Surgical Procedures; Organ; Outcome; Patients; Photophobia; Play; Population; Quality of life; Regulation; Role; Salivary Glands; Signal Transduction; Signaling Protein; Sjogren' s Syndrome; Stem cells; Symptoms; System; Techniques; Testing; Tissues; Trauma; Vision; aqueous; base; cell behavior; design; eye dryness; genome wide association study; gland development; improved; in vivo; induced pluripotent stem cell; injured; insight; irritation; lacrimal; lacrimal nerve; loss of function; mouse model; nerve supply; neuropeptide Y; novel; novel therapeutics; progenitor; receptor; regenerative; regenerative therapy; repaired; stem; stem cell therapy; transcriptomics

Project Summary/Abstract There is a critical unmet need for the application of new therapies to treat dry eye disease. A true aqueous- deficient dry eye due to inefficient lacrimal gland (LG) function is among the most common and debilitating clinical outcomes. Unfortunately, dry eye has no cure, and current treatment options target symptoms rather than resolving disease. A potential regenerative approach for restoring lacrimal function is stem cell therapy, where autologous stem/progenitor cells are transplanted into the injured organ or stem cells within the tissue are reactivated. However, to achieve this goal, we must identify LG stem/progenitor cells and understand how they are regulated. Our first objective is to resolve how nerves regulate LG homeostasis and regeneration by characterizing potential progenitor cells and determining how nerves control their differentiation into functional glandular tissue. Parasympathetic nerves regulate epithelial progenitor cells in other glandular systems, and are essential to the maintenance of lacrimal tissue. Yet, despite reduced innervation being a component of dry eye, the impact of nerve alterations on lacrimal gland homeostasis and repair (or on progenitor cells) is not known. Based on our preliminary data strongly suggesting the parasympathetic-nerve derived neuropeptide Y (NPY) is altered in patients with aqueous deficient dry eye disease (GWAS) and controls LG morphogenesis and tissue maintenance, we will test the hypothesis that NPY signaling regulates LG formation, homeostasis and regeneration by controlling stem/progenitor cell behavior. Our prediction will be addressed through 2 specific aims that seek to: 1) Define how NPY signaling regulates LG progenitor cells during development; and to 2) Determine the contribution of acinar progenitors and NPY signaling to adult LG homeostasis and regeneration. These aims will be achieved using a combination of human lacrimal glands and mouse genetics in conjunction with genetic, biochemical, immunochemical, and transcriptomic techniques. Our rationale for investigating this hypothesis is that understanding how progenitor cells are regulated during organ formation and after injury is critical if we are to repair, regenerate or replace the LG, and improve patient quality of life.

项目摘要/摘要 对于应用新疗法来治疗干眼病的情况至关重要。真正的水 由于钙效率低下（LG）功能而引起的干眼不足是最常见和令人衰弱的功能之一 临床结果。不幸的是，干眼无法治愈，当前的治疗方案针对症状而不是 而不是解决疾病。恢复泪功能的潜在再生方法是干细胞治疗， 自体茎/祖细胞被移植到组织内的受伤器官或干细胞中 重新激活。但是，为了实现这一目标，我们必须识别LG茎/祖细胞并了解 它们的监管方式。我们的第一个目标是解决神经如何调节LG稳态和 通过表征潜在的祖细胞的再生并确定神经如何控制其 分化为功能性腺组织。副交感神经调节上皮祖细胞中的细胞 其他腺体系统，对于维持泪组织至关重要。然而，尽管减少了 神经是干眼症的组成部分，神经改变对泪腺稳态和 修复（或祖细胞）尚不清楚。根据我们的初步数据，强烈建议 副交感神经造成的神经肽Y（NPY）在水性缺乏干眼症患者中发生了改变 疾病（GWAS）并控制LG形态发生和组织维持，我们将检验以下假设。 NPY信号通过控制茎/祖细胞来调节LG形成，稳态和再生 细胞行为。我们的预测将通过2个特定目的来解决：1）定义NPY如何 信号传导调节发育过程中LG祖细胞； 2）确定 腺泡祖细胞和成人LG稳态和再生的NPY信号传导。这些目标将是 使用人类泪腺和小鼠遗传学与遗传， 生化，免疫化学和转录组技术。我们研究这一假设的理由是 理解在器官形成期间和受伤后如何调节祖细胞的调节至关重要的话，如果我们是 修复，再生或替换LG并提高患者的生活质量。