Impact of aging on salivary stem cells and organ regeneration

衰老对唾液干细胞和器官再生的影响

• 批准号: 9017819
• 负责人: Sarah Monica Knox
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9017819
• 关键词: Acetylcholine; Acinar Cell; Acinus organ component; Address; Adult; Affect; Aftercare; Age; Aging; Atrophic; Autoimmune Diseases; Autologous; Behavior; Biochemical; Cell Aging; Cell Communication; Cell Cycle; Cell Therapy; Cell Transplants; Cells; Cues; DNA Damage; Data; Disease; Epigenetic Process; Epithelial; Event; Functional disorder; Future; Genetic; Genetic Identity; Genetic Techniques; Gland; Head and Neck Cancer; Homeostasis; Human; Image; Imaging Techniques; Individual; Injury; Investigation; Knowledge; Maintenance; Malignant Neoplasms; Mediating; Modeling; Modification; Molecular; Mus; Muscarinics; Natural regeneration; Nerve; Operative Surgical Procedures; Oral health; Organ; Outcome Study; Parasympathetic Nervous System; Patients; Peripheral Nerves; Population; Prevalence; Process; Proliferating; Quality of life; Radiation; Radiation therapy; Receptor Activation; Regulation; Resolution; Role; Salivary; Salivary Gland Tissue; Salivary Glands; Signal Transduction; Sjogren' s Syndrome; Societies; Stem cell transplant; Stem cells; Structure; Testing; Therapeutic; Tissue Sample; Tissues; adult stem cell; age effect; aged; aging population; base; cell age; cell behavior; cholinergic; chromatin immunoprecipitation; deep sequencing; exhaustion; improved; improved functioning; injured; middle age; nerve supply; organ regeneration; progenitor; public health relevance; radiation-induced injury; regenerative; repaired; research study; response; restoration; senescence; stem; stem cell niche; stem cell therapy; success; tissue regeneration

 DESCRIPTION (provided by applicant): Salivary gland dysfunction occurs as a result of pathological injury after radiotherapy for head and neck cancer as well as due to the autoimmune disease Sjögren's Syndrome and significantly compromises the oral health and quality of life of patients. A potential regenerative approach for restoring salivary function is sem cell therapy, where autologous stem/progenitor cells are transplanted into the injured organ or stem cells within the tissue are reactivated. However, despite the vast majority of patients with salivary dysfunction aged 45yrs or older and the well described adverse alterations in salivary gland structure and function that occurs with increasing age, the effects of aging on stem cell behavior during salivary gland homeostasis and regeneration are not known. In this application we propose to determine the impact of aging on the homeostatic and regenerative function of salivary progenitor cells and their regulation by the parasympathetic nervous system. Parasympathetic nerves are essential to salivary function and regeneration, as well as for the maintenance of epithelial progenitor cells, but very little is known regarding the influence of aging on the functional innervation of these organs. Given that aging is often associated with acinar atrophy and reduced peripheral nerve function, we hypothesize that aging disrupts cholinergic-stem cell communication required to maintain tissue homeostasis and mediate organ regeneration after injury. In this proposal we will address our central hypothesis via two specific aims: 1) Define the effect of aging on the homeostatic and regenerative capacity of SOX2+ progenitor cells and their regulation by parasympathetic nerves and 2) Identify molecular and phenotypic alterations in SOX2+ progenitor cells during aging. These aims will be achieved using a combination of human salivary glands and mouse genetics in conjunction with genetic, biochemical, immunochemical, and high resolution imaging techniques. Our rationale for investigating this hypothesis is that understanding the effects of aging on the homeostastic and regenerative capacity of stem/progenitor cells and on processes that regulate their behavior is vital to their therapeutic application in reversing salivary dysfunction.

 描述（由适用提供）：唾液腺功能障碍是由于放射疗法治疗头颈癌后患者受伤以及由于Sjögren综合征的自身免疫性疾病而导致的，并严重损害了患者的口腔健康和生活质量。恢复唾液功能的潜在再生方法是SEM细胞疗法，其中自体茎/祖细胞被移植到组织内的受伤器官或干细胞中。然而，尽管绝大多数患有45岁或45岁或以上的唾液功能障碍的患者，并且随着年龄的增长而发生的唾液腺结构和功能的不利变化，但尚不知道衰老对唾液腺稳态和再生过程中干细胞行为的影响。在此应用中，我们建议确定衰老对唾液祖细胞的稳态和再生功能的影响及其对副交感神经系统的调节。副交感神经系统对于唾液功能和再生以及上皮祖细胞的维持至关重要，但是关于衰老对这些器官功能神经的影响，知之甚少。鉴于衰老通常与腺泡萎缩有关并降低周围神经功能，我们假设衰老会破坏维持组织稳态所需的胆碱能 - 茎的通信，并介导受伤后的器官再生。在该提案中，我们将通过两个具体目的解决我们的中心假设：1）定义衰老对Sox2+祖细胞的稳态和再生能力的影响，以及通过副交感神经系统调节，并通过副交感神经系统和2）确定衰老过程中Sox2+祖细胞的分子和表型改变。这些目标将通过人类唾液腺和小鼠遗传学以及遗传，生化，免疫化学和高分辨率成像技术结合来实现。我们研究这一假设的理由是，了解老化对茎/祖细胞的稳态和再生能力的影响以及调节其行为的过程对扭转唾液功能障碍的治疗应用至关重要。