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Reversing Epidermal Stem Cell Aging: Role of Bmi-1 and the Stem Cell Niche

逆转表皮干细胞衰老：Bmi-1 和干细胞生态位的作用

基本信息

批准号：
8142144
负责人：
RUBY GHADIALLY
金额：
$ 16.01万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-10 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8142144
关键词：
Abbreviations Aging B-Cell Lymphomas B-Lymphocytes Biological Assay Cell Aging Cell Cycle Cells Contusions DNA Methylation Decubitus ulcer Dermal Elderly Environment Environmental Risk Factor Epidermis Epigenetic Process Fibroblasts Frequencies Gene Expression Goals Healed Homeostasis Impaired wound healing Individual Infectious Skin Diseases Intrinsic factor Knockout Mice Knowledge Lead Leg Ulcer Maintenance Methods Moloney Leukemia Virus Morbidity - disease rate Mus Muscle satellite cell Phenotype Polycomb Predisposition Premature aging syndrome Proteins Reverse Transcriptase Polymerase Chain Reaction Rodent Role Skeletal Muscle Skin Stem cells Suppressor Genes Surgical wound Tissue Engineering Tissues Transcript Transplantation Wound Healing age related aged cell age healing improved in vivo keratinocyte member mortality normal aging overexpression premature prevent progenitor public health relevance self-renewal senescence stem cell differentiation stem cell division stem cell niche

项目摘要

DESCRIPTION (provided by applicant): Impaired wound healing, susceptibility to skin breakdown and skin fragility lead to skin infections and considerable morbidity and mortality in the US. Our recent study shows that while no significant difference in epidermal stem cell frequency could be detected with aging, the proliferative capacity of individual epidermal stem cells was reduced. Also, transit amplifying cell frequency was greater in the aged, cell cycle duration was increased, and premature progenitor differentiation was observed. Our HYPOTHESIS is that Bmi-1 has a key role in the altered differentiation, proliferation, and symmetric divisions of aged EpiSCs and that intrinsic (Bmi-1) and/or extrinsic (niche) alterations can partially or completely restore the alterations in Bmi-1 expression, differentiation, proliferation, and symmetric division. The long-term goal of this project is to understand the mechanisms that underlie the alterations in epidermal stem cells and their niche with aging. This knowledge will be used to improve wound healing in the aged and for tissue engineering applications. SPECIFIC AIMS: In this proposal we will study the roles of both intrinsic (Bmi-1/p16) and extrinsic/environmental influences on epidermal stem cell aging. In Aim 1 we will optimize and complete our assay of the differences between aged and young EpiSCs and then investigate whether the epidermal stem cells of Bmi-1 knockout mice show a premature aging skin phenotype, (premature differentiation, decreased proliferation, extended cell cycle, increased symmetric division and increased p16 expression). We will then overexpress Bmi-1 in aged epidermal stem cells to determine whether the aging phenotype can be rejuvenated with Bmi-1 overexpression. In Aim 2 we will determine the effects of extrinsic factors, both local and systemic, on the aging of epidermal stem cells, and whether the premature differentiation, decreased proliferative capacity, increased cell cycle, increased symmetric division and decreased Bmi-1 can be reversed with a young local and/or systemic environment. These studies will be performed in a transplantation assay that allows us to look at the effects of local and systemic factors on individual progenitor cells. SIGNIFICANCE: Modifying age-related functional changes in EpiSCs through alteration of Bmi-1/p16 status could be used for retention of proliferative potential and suppression of terminal differentiation. Also better understanding environmental influences on EpiSCs would determine potential therapies to improve aged epidermal function. Great benefits for the elderly would include preventing skin breakdown/fragility (e.g. bedsores, bruising, tearing) and improved treatment of wounds (leg ulcers and slow healing surgical wounds). PUBLIC HEALTH RELEVANCE: Impaired wound healing, susceptibility to skin breakdown and skin fragility lead to skin infections and considerable morbidity and mortality in the US. In this proposal we will study the roles of both intrinsic (Bmi- 1/p16) and environmental influences on epidermal stem cell aging. Modifying age-related functional changes in EpiSCs through alteration of Bmi-1/p16 status could be used for retention of proliferative potential and suppression of terminal differentiation. Also better understanding environmental influences on EpiSCs would determine potential therapies to improve aged epidermal function. Benefits for the elderly would include preventing skin breakdown/fragility (e.g. bedsores, bruising, tearing) and improved treatment of wounds (leg ulcers and surgical wounds).

描述（由申请人提供）：在美国，伤口愈合受损、皮肤易破裂和皮肤脆弱导致皮肤感染和相当高的发病率和死亡率。我们最近的研究表明，虽然表皮干细胞的频率随年龄的增长没有显著差异，但单个表皮干细胞的增殖能力降低了。随着年龄的增长，转运扩增细胞频率增加，细胞周期延长，祖细胞早分化。我们的假设是，Bmi-1在衰老EpiSCs的分化、增殖和对称分裂中起关键作用，内在（Bmi-1）和/或外在（生态位）改变可以部分或完全恢复Bmi-1表达、分化、增殖和对称分裂的改变。该项目的长期目标是了解表皮干细胞及其生态位随年龄变化的机制。这些知识将用于改善老年人的伤口愈合和组织工程应用。具体目的：在本研究中，我们将研究内在（Bmi-1/p16）和外在/环境影响对表皮干细胞衰老的作用。在Aim 1中，我们将优化并完成老年和年轻EpiSCs之间差异的分析，然后研究Bmi-1敲除小鼠的表皮干细胞是否表现出早衰皮肤表型（过早分化、增殖减少、细胞周期延长、对称分裂增加和p16表达增加）。然后，我们将在衰老的表皮干细胞中过表达Bmi-1，以确定Bmi-1过表达是否可以使衰老表型恢复活力。在Aim 2中，我们将确定外部因素（局部和全身）对表皮干细胞衰老的影响，以及过早分化、增殖能力下降、细胞周期增加、对称分裂增加和Bmi-1下降是否可以在年轻的局部和/或全身环境中逆转。这些研究将在移植试验中进行，使我们能够观察局部和全身因素对单个祖细胞的影响。意义：通过改变Bmi-1/p16状态来改变年龄相关的EpiSCs功能变化，可用于保留增殖潜能和抑制终末分化。此外，更好地了解环境对EpiSCs的影响将确定改善衰老表皮功能的潜在疗法。对老年人的巨大好处包括防止皮肤破裂/脆弱（例如褥疮、瘀伤、撕裂）和改善伤口治疗（腿部溃疡和愈合缓慢的外科伤口）。