Molecular Mechanisms in Sweat Gland Development

汗腺发育的分子机制

• 批准号: 8996554
• 负责人: Catherine Pei-Ju Lu
• 金额: $ 12.4万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-21 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996554
• 关键词: Affect; Anhidrotic Ectodermal Dysplasia; Area; Biology; Body Temperature; Burn injury; Cells; Data; Defect; Development; Disease; Duct (organ) structure; Eccrine Glands; Ectodermal Dysplasia; Environment; Epidermis; Epithelial; Epithelial Cells; Equilibrium; Equipment; Event; Faculty; Failure; Fever; Future; Gene Expression; Gene Expression Profile; Genes; Gland; Goals; Hair follicle structure; Health; Heating; Human; Inherited; Knock-in Mouse; Knockout Mice; Knowledge; Laboratories; LacZ Genes; Life; Location; Maintenance; Mentored Research Scientist Development Award; Mentors; Mesenchymal; Mesenchyme; Molecular; Morphogenesis; Mus; Mutation; Natural regeneration; Pathway interactions; Patients; Phenotype; Physiologic Thermoregulation; Positioning Attribute; Postdoctoral Fellow; Quality of life; Reporter; Research; Research Personnel; Research Proposals; Resources; Risk; Role; Signal Transduction; Skin; Skin graft; Sorting - Cell Movement; Specific qualifier value; Staging; Sweat; Sweat Glands; Sweating; Training; Training Technics; Universities; Up-Regulation; Water; Work; appendage; base; career development; cell type; comparative; differential expression; genome-wide; gland development; in utero; innovation; insight; knock-down; novel; overexpression; progenitor; programs; skills; skin disorder; small hairpin RNA; stem cell biology; transcriptome sequencing

 DESCRIPTION (provided by applicant): I have been devoted and aiming to establish an independent and innovative research program in epithelial stem cell biology and to study skin-related diseases. The K01 mentored research scientist development award will present great opportunities for me to acquire additional skills and expertise that are essential for my transitio into an independent position. As a postdoctoral fellow in the laboratory of Dr. Elaine Fuchs at The Rockefeller University, I find myself in a premium scientific environment that fully supports my career development and provides all the equipments, resources, facilities, and trainings that are necessary for me to complete this proposed work successfully and to transition into an independent faculty position. Eccrine sweat glands are widely distributed in most areas of human skin, and its proper maintenance and functioning is crucial for optimal thermoregulation and water balance throughout our lifetime. Patients born with Hypohidrotic (Anhydrotic) Ectodermal Dysplasia (HED) have defects in sweat gland development and suffer from constant high fever due to inability to dissipate heat efficiently, and their lives are at risk. The long-tem objective of this proposed research is to understand the molecular mechanisms in sweat gland development, more specifically, the epithelial-mesenchymal signaling crosstalk that are involved. Knowledge acquired from this proposed research will contribute to future sweat gland regeneration that may benefit patients with sweat gland deficiency. Previous studies on Human HED patients revealed that mutations in WNT10a, in addition to components in EDA pathways, cause defective sweat gland development. As EDA pathway has been well characterized to be indispensable for initiation of various ectodermal appendages, the role of Wnt signaling in the context of sweat gland development is unknown. In addition, epithelial-mesenchymal signaling crosstalk has been shown to dictate epithelial cell fate, but exact signaling components that are involved remain elusive. Based on prior knowledge, I hypothesize that Wnt signaling triggers changes in the expression of secreting factors from mesenchyme, which then in turn determine the cell fate of epithelial progenitors to derive sweat glands. Specifically in this research proposal, I plan to: 1) Characterize the temporal and spatial activities of Wnt signaling during sweat gland initiation and morphogenesis; 2) Identify mesenchymal signals that specify sweat gland cell fate and support glandular differentiation; 3) Determine whether BMP-Shh antagonism occurs in the context of sweat gland development. With the support of a K01 award, I will obtain the necessary training and techniques essential for my transition into an independent research position, and expand my expertise and capability to perform research of high quality. I will also develop additional skills on networking, management, and mentoring, which together will equip me to achieve my future research goals as an independent investigator.

 描述（由申请人提供）：我一直致力于建立上皮干细胞生物学方面的独立创新研究项目并研究皮肤相关疾病，K01 指导研究科学家发展奖将为我提供获得更多额外机会的绝佳机会。作为洛克菲勒大学 Elaine Fuchs 博士实验室的博士后研究员，我发现自己处于一个优质的科学环境中，这对我过渡到独立职位至关重要。成功完成这项拟议工作并过渡到独立教职职位所需的设备、资源、设施和培训小汗腺广泛分布在人体皮肤的大部分区域，其适当的维护和功能对于我来说至关重要。一生中最佳的体温调节和水平衡。出生时患有少汗（无水）外胚层发育不良（HED）的患者存在汗腺发育缺陷，并且由于无法有效散热而持续发高烧，从而影响他们的生命。这项研究的长期目标是了解汗腺发育的分子机制，更具体地说，从这项研究中获得的知识将有助于未来的汗腺再生。先前对人类 HED 患者的研究表明，除了 EDA 通路的组成部分外，WNT10a 的突变也会导致汗腺发育缺陷，因为 EDA 通路已被充分表征为启动过程中不可或缺的。对于各种外胚层附属物，Wnt 信号传导在汗腺发育中的作用尚不清楚。此外，上皮-间质信号传导串扰已被证明决定上皮细胞的命运，但所涉及的确切信号传导成分仍然难以捉摸。据了解，我认为 Wnt 信号传导会触发间充质分泌因子表达的变化，进而决定上皮祖细胞的细胞命运，以产生汗腺。根据研究计划，我计划：1) 表征汗腺启动和形态发生过程中 Wnt 信号传导的时间和空间活动；2) 识别指定汗腺细胞命运和支持腺体分化的间充质信号；3) 确定是否发生 BMP-Shh 拮抗作用。在 K01 奖项的支持下，我将获得过渡到独立研究职位所需的必要培训和技术，并扩展我的专业知识和能力，以进行高质量的研究。还将培养有关网络、管理和指导的额外技能，这些技能将使我能够实现作为独立研究者的未来研究目标。