Molecular Mechanisms in Sweat Gland Development

 简介(申请人提供)：我一直致力于并致力于建立一个独立和创新的上皮干细胞生物学研究项目，并研究与皮肤相关的疾病。K01指导研究科学家发展奖将为我提供获得额外技能和专业知识的绝佳机会，这些技能和专业知识是我过渡到独立职位所必需的。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，这个环境完全支持我的职业发展，并提供成功完成这项拟议工作并过渡到独立教师职位所需的所有设备、资源、设施和培训。汗腺广泛分布于人类皮肤的大部分区域，其适当的维护和功能对于我们一生中最佳的体温调节和水分平衡至关重要。先天性少汗性(无水)外胚层发育不良(HED)患者汗腺发育缺陷，因不能有效散热而持续高热，生命危险。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，是涉及到的上皮-间充质信号串扰。从这项拟议的研究中获得的知识将有助于未来汗腺的再生，这可能会使汗腺缺陷患者受益。之前对人类HED患者的研究表明，WNT10a的突变，除了EDA途径的成分外，还会导致汗腺发育缺陷。由于EDA途径被认为是各种外胚层附属物启动所必需的，Wnt信号在汗腺发育中的作用尚不清楚。此外，上皮-间充质信号串扰已被证明决定上皮细胞的命运，但涉及的确切信号成分仍然难以捉摸。基于先验知识，我假设Wnt信号触发间充质分泌因子表达的变化，继而决定上皮祖细胞衍生汗腺的细胞命运。具体地说，在这项研究中，我计划：1)表征Wnt信号在汗腺起始和形态发生过程中的时空活动；2)识别决定汗腺细胞命运和支持腺体分化的间质信号；3)确定BMP-Shh拮抗是否发生在汗腺发育的背景下。在K01奖项的支持下，我将获得必要的培训和技术，以过渡到独立的研究职位，并扩大我的专业知识和能力，进行高质量的研究。我还将在网络、管理和指导方面培养更多的技能，这些技能加在一起将使我成为一名独立调查员，从而实现我未来的研究目标。

 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.