Mechanisms of Altered Skin Re-Epithelialization in Aging

衰老过程中皮肤再上皮化改变的机制

基本信息

批准号：
8502171
负责人：
Laure Rittie
金额：
$ 9.68万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2010-09-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8502171
关键词：
Abbreviations Age-Years Aging Amphotericin B Biochemical Biological Biological Process Biology Biometry Cell Proliferation Cell Size Cells Characteristics Clinical Clinical Research Code Comorbidity Complement Complementary DNA Complex Culture Techniques Cutaneous Cytoskeleton Data Dermatology Dermis Disease Down-Regulation Educational workshop Elderly Epidermis Epithelial Ethics Faculty Future Growth Hair follicle structure Hereditary Disease Human Human Volunteers Hyperplasia Impaired wound healing Impairment In Vitro Individual Institution Keratin Learning Malignant Neoplasms Measurement Mediating Mentors Methods Michigan Modeling Molecular Molecular Biology Mutate Natural regeneration Organ Pathologic Penicillins Phosphorylation Phosphorylation Site Play Population Postdoctoral Fellow Production Productivity Property Proteins Psoriasis Publishing Research Research Personnel Research Project Grants Resources Reverse Transcription Role Scientist Site Skin Skin Aging Sodium Chloride Solutions Staging Stratum Basale Streptomycin Structure Surface Testing Tetanus Helper Peptide Tetracyclines Therapeutic Time Training Universities Untranslated Regions Work Wound Healing age effect age related aged base career design enhanced green fluorescent protein experience improved in vivo innovation keratinocyte mTOR protein member migration mutant novel overexpression pre-doctoral premature programs protein expression regenerative response skills skin disorder stem cell niche wound young adult

项目摘要

DESCRIPTION (provided by applicant): I am a non-tenure track junior faculty at my Institution, and have previous pre- and post-doctoral research experience in Dermatology. I have been uniquely trained in clinical research in the field of skin aging and photoaging, and have a published record of productivity in this field. The proposed project is designed to provide me with the additional training I need to develop an innovative and independent research project, and establish myself as an independent translational researcher. Impaired wound healing is a common clinical problem in the elderly population. Clinical observations indicate that wound healing is delayed in aged compared to young skin, and that regenerated skin is highly susceptible to further tearing in elderly individuals. The molecular and cellular basis for these observations remains unknown. Lack of experimental data in humans originates from the difficulties of isolating the effects of co-morbidity factors in an aged population, and ethical considerations associated with wound studies in humans in vivo. To overcome these obstacles, we have developed a method to generate controlled, safe, and reproducible wounds in healthy young (<40 years) and aged (>70 years) human volunteers. Our preliminary data demonstrate that wound healing response in the aged is not "slow", but rather abbreviated or interrupted, compared to young adults. We found that premature termination of the wound healing response is due to early cessation of epidermal cell proliferation in aged human skin. The specific focus of this project is to investigate the molecular mechanisms that cause this age-dependent cessation of keratinocyte regenerative capacity. Based on our preliminary data obtained by direct measurements in young and aged human skin, we hypothesize that "activation" keratins, major cytoskeletal components induced in wounded skin, play important functions in regulating keratinocyte regenerative capacity during normal wound repair, and are defective in aged skin. Our specific aims are designed to establish a working model, and directly test this hypothesis. In addition to outstanding institutional resources and support, I will benefit from the help of an exceptional mentoring team on this project. I will be trained in state-of-the art molecular biology and organotypic culture techniques by my co-mentor, advised on the specifics of keratin biology by my consultant, and guided to independence in the field of skin aging by my sponsor. All members of my mentoring team are well-established and respected scientists, world experts in their respective fields, and confirmed mentors. My learning activities will also include initiation to the biostatistics related to my specific project, and attendance to workshops aimed at preparing my future independent academic career. The long-term objective of my research is to understand the molecular mechanisms that are responsible for impaired wound healing during aging, and thereby develop therapeutic solutions to improve the quality of wound repair in the elderly. In addition to testing our hypothesis regarding the mechanism of age-dependent alteration of wound healing in human skin, our proposed studies will likely provide useful information on the functional significance of "activation" keratin expression during re-epithelialization. Given that "activation" keratin overexpression is also a hallmark of multiple hyperproliferative skin diseases, genetic conditions, and epithelial cancers, our results are expected to be directly applicable to many conditions and diseases, in skin as well as in other organs.

描述（由申请人提供）：我是我所在机构的非终身教职初级教师，之前有皮肤病学博士前和博士后研究经验。我接受过皮肤老化和光老化领域临床研究的独特培训，并在该领域发表了生产力记录。拟议的项目旨在为我提供开发创新和独立研究项目所需的额外培训，并使我自己成为一名独立的转化研究员。伤口愈合受损是老年人群中常见的临床问题。临床观察表明，与年轻皮肤相比，老年人的伤口愈合延迟，并且老年人的再生皮肤极易进一步撕裂。这些观察结果的分子和细胞基础仍然未知。人体实验数据的缺乏源于在老年人群中分离共病因素的影响的困难，以及与人体体内伤口研究相关的伦理考虑。为了克服这些障碍，我们开发了一种方法，可以在健康的年轻（<40 岁）和老年人（>70 岁）人类志愿者身上产生受控、安全和可重复的伤口。我们的初步数据表明，与年轻人相比，老年人的伤口愈合反应并不“缓慢”，而是缩短或中断。我们发现，伤口愈合反应的提前终止是由于衰老的人类皮肤中表皮细胞增殖的提前停止造成的。该项目的具体重点是研究导致角质形成细胞再生能力随年龄而停止的分子机制。根据我们通过对年轻和老年人类皮肤进行直接测量获得的初步数据，我们假设“活化”角蛋白（受伤皮肤中诱导的主要细胞骨架成分）在正常伤口修复过程中调节角质形成细胞再生能力方面发挥重要作用，并且在老年皮肤中存在缺陷。皮肤。我们的具体目标是建立一个工作模型，并直接检验这个假设。除了出色的机构资源和支持之外，我还将受益于该项目的优秀指导团队的帮助。我将由我的共同导师接受最先进的分子生物学和器官培养技术的培训，由我的顾问提供有关角蛋白生物学细节的建议，并由我的资助者指导我在皮肤老化领域取得独立。我的导师团队的所有成员都是知名且受人尊敬的科学家、各自领域的世界专家和公认的导师。我的学习活动还包括开始与我的具体项目相关的生物统计学，以及参加旨在为我未来的独立学术生涯做好准备的研讨会。我研究的长期目标是了解衰老过程中伤口愈合受损的分子机制，从而开发治疗方案来提高老年人伤口修复的质量。除了检验我们关于人类皮肤伤口愈合随年龄变化的机制的假设之外，我们提出的研究可能会提供关于上皮再形成过程中“激活”角蛋白表达的功能意义的有用信息。鉴于“激活”角蛋白过度表达也是多种过度增殖性皮肤病、遗传性疾病和上皮癌的标志，我们的结果预计将直接适用于皮肤以及其他器官的许多病症和疾病。