Age-related olfactory loss: mechanisms and treatment options

与年龄相关的嗅觉丧失：机制和治疗选择

基本信息

批准号：
8786272
负责人：
JAMES E. SCHWOB
金额：
$ 59.47万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8786272
关键词：
A Mouse Abbreviations Ablation Address Afferent Neurons Age Aging Antibodies Apical Area Basal Cell Biological Assay Birth Brain Breeding Cell Aging Cell Line Cell physiology Cells Cessation of life Chronic Colony-Forming Units Assay Diphtheria Toxin Disease Doxycycline Environment Epithelial Epithelium Experimental Models Failure Functional disorder Genetic Genetic Models Genetic Recombination Genetic Transcription Genotype Grant Human In Vitro Injury Interneurons Investigation Knock-out Lead Lesion Longevity Maps Measures Metaplasia Mitotic Activity Modeling Multipotent Stem Cells Mus Natural regeneration Neurons Nutritional status Odorant Receptors Olfactory Basal Cell Olfactory Epithelium Operative Surgical Procedures Pathology Patients Population Production Quality of life Recovery Rejuvenation Research Reserve Stem Cell Response Elements Risk Sensory Staining method Stains Stem cells Stress Structure Structure of respiratory epithelium Synapses System Tamoxifen Testing Tetanus Helper Peptide Tetracyclines Therapeutic Thymidine Tissues Toxin Trans-Activators Transgenic Mice Transplantation Tyrosine 3-Monooxygenase Work age related aged analog base cell age density design exhaust exhaustion falls functional status in vivo injured methyl bromide mouse model nerve supply neurogenesis olfactory bulb premature progenitor public health relevance reconstitution reinnervation repaired research study restoration stem stem cell population sustentacular cell transcription factor

项目摘要

DESCRIPTION (provided by applicant): Abnormalities of stem cell function and/or the destruction of stem cells lead to an olfactory epithelium (OE) that remains olfactory (including a full apical lining composed of sustentacular cells), but one that has no neurons (OSNs), no globose basal cells (GBCs), and no ongoing neurogenesis - a condition that we term neurogenic exhaustion. We have developed a mouse model based on the expression of Diptheria toxin subunit A (DTA) in OMP-expressing mature OSNs that causes a tetracycline-reversible abbreviation of normal neuronal life-span and causes proliferation to accelerate at first, but then eventually dissipate. Aim 1 proposes experiments to understand when and how GBC stem cell failure develops by analyzing the GBC population as a function of age, as well as its capacity to generate olfactospheres in culture and engraft after transplantation - both of the latter phenomena assay the functional status of the progenitor population. Aim 2 shifts its focus to a second type of olfactory stem cell called horizontal basal cells (HBCs). Unlike GBCs, the HBCs persist in aneuronal OE, but are not functioning as multipotent progenitors/stem cells as they can do when the epithelium is directly injured and more than just neurons are dying. The HBCs will be activated out of their dormancy by a conditional knock-out strategy aimed at the transcription factor p63. We will test whether the GBCs that originate from the HBCs will persist and repopulate the epithelium. Aim 3 will assay whether restoration of the neuronal population, in this case by taking advantage of the reversibility of our DTA-driven experimental model and stopping the premature death of the neurons, results in correct reinnervation of the olfactory bulb. The experiments in Aim 3 will establish whether it is realistic to expect that the rejuvenation of the stem and progenitor populations and the reestablishment of neuronal input to the CNS can restore appropriate function. Currently, the complete lack of therapeutic options for patients with olfactory disease provides a strong justification for pursuing this research.

描述（由申请人提供）：干细胞功能异常和/或干细胞破坏导致嗅觉上皮（OE）保留嗅觉（包括由支持细胞组成的完整顶端衬里），但没有神经元（ OSN），没有球状基底细胞（GBC），也没有持续的神经发生——我们称之为神经源性衰竭。我们开发了一种基于白喉毒素亚基 A (DTA) 在表达 OMP 的成熟 OSN 中表达的小鼠模型，该模型会导致正常神经元寿命的四环素可逆性缩短，并首先导致增殖加速，但随后最终消散。目标 1 提出进行实验，通过分析 GBC 群体作为年龄的函数，以及其在培养物和移植后植入中生成嗅球的能力，来了解 GBC 干细胞衰竭何时以及如何发生——后两种现象都测定了 GBC 干细胞的功能状态。祖先群体。目标 2 将重点转移到第二种类型的嗅觉干细胞，称为水平基底细胞 (HBC)。与 GBC 不同，HBC 持续存在于神经元 OE 中，但不能像上皮直接损伤且不仅仅是神经元死亡时那样发挥多能祖细胞/干细胞的作用。 HBC 将通过针对转录因子 p63 的条件敲除策略从休眠状态中被激活。我们将测试源自 HBC 的 GBC 是否会持续存在并重新填充上皮细胞。目标 3 将测定神经元群的恢复（在这种情况下，通过利用 DTA 驱动的实验模型的可逆性并阻止神经元过早死亡）是否会导致嗅球的正确神经支配。目标 3 中的实验将确定干细胞和祖细胞群的再生以及中枢神经系统神经元输入的重建是否可以恢复适当的功能。目前，嗅觉疾病患者完全缺乏治疗选择，这为开展这项研究提供了强有力的理由。