The Role of Notch2 and Notch3 in Cutaneous Wound Healing

职位描述(申请人提供)：应聘者：我的职业目标是成为创伤愈合研究和皮肤创伤再生疗法发展的领导者。为了实现这一目标，我将在皮肤生物学和缺口信号以及研究过程中的伦理学方面接受基础科学的强化培训。这将包括正式的课程作业，一对一的指导，在实验室会议上的陈述，系和大学范围内的研讨会和全国会议。我将带领一个新成立的研究团队研究皮肤生物学，为了解皮肤伤口愈合的机制奠定科学基础。我将在不晚于获奖期的第四年提交RO1申请。最后，我将寻求国家组织的领导职位，以加强这一领域的合作努力，并直接关注和提供资源，为这一问题制定治疗方法和解决办法。所有这些步骤都将帮助我成功地过渡到独立。环境：威斯康星大学是美国一流的研究机构之一，校园里有800多名生物学家。在联邦政府资助和外科科学家的职业发展方面，外科系享有全国最高声誉之一。该部调动了大量资源，为金博士的职业发展作出承诺，包括保证启动资金(220000美元)和每年9个月的受保护时间。此外，金博士还将得到本校两位杰出的科学家和非常成功的导师(Allen-Hoffmann博士和Chen博士)以及其他杰出教职员工的指导。这些组成部分将为他提供一个最佳的研究环境，确保他成功地过渡到独立。研究：我的长期目标是作为一名临床科学家发展独立的研究生涯，专注于开发用于治疗皮肤伤口的新型有效治疗干预措施。本应用的目的是确定Notch家族在人和小鼠皮肤伤口愈合中的分子机制。我们的中心假设是，皮肤特异性Notch家族成员通过对表皮内增殖、角质形成细胞分化和分层的不同调控，在皮肤创伤愈合中发挥重要作用。我们基于我们的初步数据和Kopan，Dotto，Radtke，Fuchs和其他人发表的工作提出了这一假说。拟议的研究计划的基本原理是，它有望对皮肤伤口愈合的分子机制产生新的见解，通过它可以开发出临床相关的治疗干预措施来治疗皮肤伤口，同时，为我提供建立作为临床科学家的独立性的手段。我们已经做好了继续这些研究的准备，因为我们机构致力于开发伤口愈合的新策略和独立的临床医生科学家。我已经建立了一个指导团队和合作者，他们拥有指导我获得独立研究项目所需的所有技能。我们将通过追求以下具体目标来实现我们的目标：具体目标#1：利用嵌合K14特异性Notch1、2或3基因敲除小鼠，研究Notch家族在皮肤伤口愈合中的作用。我们的工作假设是，在K14特异性Notch基因敲除小鼠中产生的伤口减少了闭合率和屏障功能。具体目标#2：以单层和器官培养为模型，研究Notch家族在皮肤伤口闭合和伤口愈合中屏障功能建立中的作用。我们的工作假设是，抑制缺口通路将导致伤口延迟闭合，并降低伤口的屏障功能，而重新激活缺口通路将增加闭合率，改善愈合的器质性皮肤的屏障功能。具体目标#3：描述缺口激活的能力 利用嵌合K14特异性Notch1、2或3基因敲除小鼠修复体内伤口。我们的工作假设是，激活缺口将增加闭合率，改善创伤皮肤的屏障功能。

DESCRIPTION (provided by applicant): Candidate: My career goals are to become a leader in the study of wound healing and the development of regenerative therapies for cutaneous wounds. To achieve this I will undergo intensive training in the basic sciences in cutaneous biology and notch signaling as well as ethics in the conduct of research. This will include formal coursework, one-on-one mentorship, presentations at lab meetings, department and University-wide seminars and national meetings. I will lead a nascent team of investigators in the study of cutaneous biology to develop a scientific foundation for understanding the mechanisms of cutaneous wound healing. I will submit an RO1 application no later than year 4 of the award period. Finally, I will seek leadership positions in national organizations in order to enhance collaborative efforts in this area as well as direct attention and resources towards developing therapies and solutions for this problem. All of these steps will facilitate my successful transitin to independence. Environment: The University of Wisconsin is one of the premier research institutions in the United States with over 800 biologists on campus. The Department of Surgery enjoys a reputation as one of the top in the country in terms of federal funding and career development of surgeon-scientists. The Department has mobilized its significant resources in making a commitment to Dr. King's career development including guarantees for start-up funds ($220,000) and 9 months of protected time per year. In addition, Dr. King will be mentored by two exceptional scientists and very successful mentors on this campus (Drs. Allen-Hoffmann and Chen) as well as other outstanding faculty. These components will provide him with an optimal research environment that will ensure that his transition to independence is successful. Research: My long-term goal is to develop an independent research career as a clinician scientist focused on the development of novel and effective therapeutic interventions for the treatment of cutaneous wounds. The objective of this application is to determine the molecular mechanism of the Notch family in human and murine cutaneous wound healing. Our central hypothesis is that skin specific Notch family members play a significant role in cutaneous wound healing by differential regulation of proliferation, keratinocyte differentiation and stratificatio within the epidermis. We have developed this hypothesis based upon our preliminary data and the published work of Kopan, Dotto, Radtke, Fuchs and others The rationale for the proposed research program is that it expected to yield new insights into the molecular mechanisms of cutaneous wound healing through which a clinically relevant therapeutic intervention could be developed for the treatment of cutaneous wounds, while at the same time, providing me the means of establishing independence as a clinician scientist. We are well prepared to pursue these studies because of the commitment of our institution to develop both novel strategies for wound healing and independent clinician scientists. I have created a mentoring team and collaborators with all of the skills needed to guide me in my pursuit to gain an independent research program. We will achieve our objectives through the pursuit of the following specific aims: Specific Aim #1: Investigate the role of the Notch family in cutaneous wound healing utilizing chimeric K14 specific Notch1, 2, or 3 knockout mice. Our working hypothesis is that wounds created in K14 specific Notch knockout mice have decreased rates of closure and decreased barrier function. Specific Aim #2: Characterize the role of the Notch family in cutaneous wound closure and establishment of barrier function in wound healing modeled in monolayer and organotypic culture. Our working hypothesis is that inhibition of the notch pathway will lead to delayed closure, and decreased barrier function in wounds and that re-activation of the notch pathway will increase the rate of closure and improve the barrier function of the "healed" organotypic skin. Specific Aim #3: Characterize the ability of notch activation to heal in vivo wounds utilizing chimeric K14 specific Notch1, 2, or 3 knockout mice. Our working hypothesis is that activating notch will increase the rate of closure and improve the barrier function of the wounded skin.