Dissect stress response in skin epithelial wounding and hyperproliferative disorders

项目摘要 在我的博士学位期间，我使用骨骼肌发生作为我的模型来剖析信号转导和基因 监管机制。我已经获得了广泛的分子生物学和 生化工具，积累了关于遗传小鼠模型的关键经验，并开发了关键和 具备实验生物学方面的分析思维能力。我也开始意识到功能基因组学的力量， 到目前为止，我为期4.5年的博士后培训主要是询问皮肤肿瘤发生的分子驱动因素 以干细胞为燃料，在小鼠模型中应用功能基因组学原理，并验证了 人体临床样本和异种移植。这些培训拓宽了我的研究视野，成熟了我的 实验技能，并为我在人类疾病中提出重要问题奠定了基础。 由于意外的家庭困难，我延长了我的培训，这对我来说是必要的 其他科学和学术技能，使我能够获得完全的研究自主权，并制定 创新的基础研究方案，解决发展和疾病方面的基本问题。超过了 在过去的几十年里，我们开始了解一些参与伤口修复的分子机制。我们有 还对癌症中的致癌和肿瘤抑制途径获得了实质性的见解。然而，尽管 长期以来认为癌症是一种永远不会愈合的伤口的假设，目前仍不清楚伤口和 癌症在功能上依赖于相同的压力成分，如果是这样的话，它们在哪一点上会出现分歧。这些是 我目前和未来提出的研究的主要重点。我将建立和扩展基于非 使用宫内转导CRISPR试剂的生殖系基因工程马赛克小鼠模型。这就做 应用功能基因组学方法对驾驶中应激相关基因进行优先排序和筛选 伤口修复和癌症。我将描述引导长期寻找的分叉点的分子机制。 两种应激条件之间的关系，并验证我的最佳候选应激基因的生理相关性 在人体样本中。这一知识将增加我们对细胞内分子机制的理解。 压力，并有助于改善皮肤创伤、增生性疾病和癌症的治疗方法。 在富克斯实验室、洛克菲勒大学提供的刺激气氛下，三个- 机构和更广泛的纽约科学界，我发现自己处于一个不同寻常的 环境来追求我的抱负。如果获奖，我将进一步接受1)技术技能方面的培训--测序， 高级显微镜、CRISPR技术；以及2)个人发展--写作、交流、指导、 领导力和管理。我的目标是，在K01的最后几年，以独立的土地保有权轨道 定位于顶级振动环境，特别是那些高度重视非编码生物的环境， 在那里，我将建立自己在皮肤病和癌症方面的创新、可行和可持续的研究计划。

Project Summary During my PhD, I used skeletal myogenesis as my model to dissect signal transduction and gene regulation mechanisms. I have obtained technical literacy over a wide range of molecular biology and biochemical tools, accumulated critical experience on genetic mouse models, and developed critical and analytical thinking skills in experimental biology. I also came to appreciate the power of functional genomics, My so far 4.5-year's postdoc training focuses on interrogating molecular drivers in skin tumorigenesis fueled by stem cells, applying principles of functional genomics in mouse models, and validating findings in human clinic samples and xenografts. These training had expanded my research horizon, matured my experimental skills, and laid groundwork for me to ask important questions in human diseases. As I extend my training due to unexpected family difficulties, it would be essential for me to acquire additional scientific and academic skills that will enable me to gain full research autonomy and develop an innovative basic research program addressing fundamental questions in development and diseases. Over the past decades, we start to understand some of the molecular mechanisms involved in wound repair. We have also acquired substantial insights into oncogenic and tumor suppressive pathways in cancer. However, despite the long posited hypothesis that cancer is a wound that never heals, it is still unclear whether wounds and cancer functionally rely on the same stress components and if so, at which point they diverge. These are the primary focus of my current and future proposed research. I will establish and expand tools based on non- germline genetically engineered mosaic mouse models using in utero transduced CRISPR reagents. I will apply functional genomic approaches to prioritize and screen a focused list of stress relevant genes in driving wound repair and cancer. I will delineate molecular mechanisms that steer the long sought bifurcation point between the two stress conditions, and validate the physiological relevance of top my candidate stress genes in human samples. This knowledge will add to our understanding of the molecular mechanisms during cellular stress, and help to improve therapeutic treatments in skin wounds, hyperplasic diseases, and cancer. With the stimulating atmosphere provided by the Fuchs lab, the Rockefeller University, the Tri- Institution, and the broader NYC scientific community, I found myself positioned within an exceptional environment to pursue my ambition. If awarded, I will further obtain training in 1) technical skills – sequencing, advanced microscopy, CRISPR technology; and 2) personal development – writing, communication, mentoring, leadership, and management. My goal is, during the final years of K01, land in an independent tenure-track position with top-tier vibrating environment, especially those with an intensive emphasis on non-coding biology, where I will establish my own innovative, viable and sustainable research program in skin diseases and cancer.