A cellular basis for age-related impaired tactile acuity

与年龄相关的触觉敏锐度受损的细胞基础

• 批准号: 8638126
• 负责人: DAVID M OWENS
• 金额: $ 24万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638126
• 关键词: 2 year old; Address; Age; Aging; Alleles; Apoptosis; Behavior; Biological Assay; Cell Aging; Cell physiology; Cells; Cellular biology; Cleaved cell; Complex; Cutaneous; Defect; Deterioration; Eating; Elderly; Elements; Epidermis; Frequencies; Future; Genetic; Goals; Hand; Homeostasis; Hour; Human; Implant; In Vitro; Laboratories; Life; Light; Mechanoreceptors; Mediating; Merkel Cells; Mitotic; Molecular; Mus; Natural regeneration; Nerve; Neurites; Neurosecretory Systems; Organ; Perception; Physiologic pulse; Play; Population; Quality of life; Reporter; Research Design; Rodent; Role; Sensory; Signal Pathway; Skin; Skin Aging; Somatosensory Receptor; Sorting - Cell Movement; Stem cells; Structure; Tactile; Tamoxifen; Testing; Time; Touch sensation; Transgenic Mice; Transplantation; age group; age related; aged; base; caspase-3; cell age; cell growth regulation; design; falls; grasp; in vivo; keratinocyte; mouse model; novel; progenitor; public health relevance; receptor; recombinase; reconstitution; regenerative; response; sound; success; therapeutic target; tool; young adult

DESCRIPTION (provided by applicant): It is well established that touch perception deteriorates with age and this phenomenon is accompanied by a number of structural defects in the skin including a dramatic loss of Merkel cell-neurite complexes, other tactile afferents and touch sensitivity. Deficits in touch perception are thought to contribute to the decline of postura stability and handgrip, and the resulting increase in falling frequency, which is a major factor determining quality of life and the ability to live independently for the elderly. Technical hurdle that have hindered efforts to understand the cellular and molecular basis of age-related losses in touch perception are i) the variety of somatosensory receptors and ii) the fact that mechanoreceptive end organs are scattered throughout the skin. Furthermore, information regarding putative skin progenitor populations that are responsible for maintaining the turnover of cellular mechanoreceptors that perceive light touch, such as Merkel cells, is sorely lacking. Merkel cells represent a mature neuroendocrine lineage that resides in unique structures in the epidermis of hairy skin in rodents and humans termed touch domes (TDs). Our laboratory previously identified a novel keratinocyte progenitor population localized with Merkel cells in TDs termed TD progenitor cells (TDPCs) and we demonstrated that TDPCs could give rise to the Merkel lineage both under regenerative conditions and homeostasis. To further explore the role of TDPCs in Merkel cell homeostasis, we generated a BAC transgenic mouse model in our laboratory, Krt17CreERT2 that selectively targets TDPCs in the epidermis for expression of a tamoxifen-inducible Cre recombinase while excluding mature Merkel cells. Using Krt17CreERT2 mice in combination with other Cre-inducible reporter alleles we demonstrated that i) TDPCs are permanent residents of the skin that are solely responsible for maintaining the Merkel lineage and ii) the entire pool of mature Merkel cells within the TD is turned over every two months in young adult skin. These preliminary findings establish Krt17CreERT2 mice as an excellent platform to examine how Merkel cell homeostasis may be perturbed in aged skin. The main objective of this proposal is to determine whether a decline in progenitor capacity of TDPCs underlies the age-related loss in Merkel cell-neurite complexes and diminished touch sensation. To accomplish our objective, we will employ Krt17CreERT2 mice to determine the rate of Merkel cell genesis and apoptosis in aged skin. We will also purify TDPCs from aged skin and assess their clonogenic capacity in vitro. Finally, we will transplant young adult and aged TDPCs and directly assess their ability to regenerate Merkel cells in vivo and restore tactile acuity. These studies will be critical to understanding the cellular regulation of our sense of touch, an essentil element of our ability to perceive our surroundings that is severely diminished as we age.

描述（由申请人提供）：众所周知，触摸感知随着年龄的增长而恶化，这种现象伴随着皮肤中的许多结构缺陷，包括默克尔细胞神经突配合物，其他触觉传入和触摸敏感性的巨大损失。触摸感知的缺陷被认为有助于postura稳定性和手夹的下降，以及导致的下降频率的增加，这是决定生活质量的主要因素，并且能够独立生活质量。阻碍了了解与年龄相关的损失的细胞和分子基础的努力的技术障碍是i）体感受体的种类，ii）机械感受器的终端器官散布在整个皮肤中。此外，有关假定皮肤祖细胞种群的信息，这些信息迫切缺乏感知轻触摸的细胞机械感受器的营业额，例如默克尔细胞。默克尔细胞代表一个成熟的神经内分泌谱系，该谱系位于啮齿动物和人类所谓的接触圆顶（TDS）的毛皮表皮中的独特结构中。我们的实验室先前鉴定出一种新型的角质形成细胞祖细胞种群，该祖细胞种群与默克尔细胞定位在称为TD祖细胞（TDPC）的TDS中，我们证明TDPC可以在再生条件和稳态下引起默克尔谱系。为了进一步探索TDPC在Merkel细胞稳态中的作用，我们在实验室中产生了BAC转基因小鼠模型KRT17CREERT2，该模型在表皮中有选择地靶向TDPC，以表达他莫昔芬可诱导的CRE重组酶，同时排除了成熟的Merkel细胞。使用KRT17CREERT2小鼠与其他CRE诱导的记者等位基因结合使用，我们证明，I）TDPC是皮肤的永久居民，它们完全负责维持整个Merkel细胞的整个Merkel细胞库中TD内的整个默克尔池在年轻人的年轻人皮肤中每两个月都转过了每两个月。这些初步发现将KRT17CREERT2小鼠作为一个出色的平台，以研究如何在老年皮肤中扰动默克尔细胞稳态。该提案的主要目的是确定TDPC的祖细胞能力下降是否是默克尔细胞神经岩复合物与年龄相关的损失和触摸感觉降低的基础。为了实现我们的目标，我们将采用KRT17CREERT2小鼠来确定老化皮肤中默克尔细胞的发生和凋亡的速率。我们还将从老年皮肤中净化TDPC，并在体外评估其克隆能力。最后，我们将移植年轻的成人和老年TDPC，并直接评估他们在体内再生默克尔细胞并恢复触觉敏锐度的能力。这些研究对于理解我们的接触感的细胞调节至关重要，这是我们感知周围环境能力的当时元素，随着年龄的增长，我们的周围环境会大大减少。