The Role of Notch2 and Notch3 in Cutaneous Wound Healing

Notch2 和 Notch3 在皮肤伤口愈合中的作用

• 批准号: 8891446
• 负责人: Timothy W King
• 金额: $ 4.64万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-06 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891446
• 关键词: Adult; Area; Award; Basic Science; Biology; Cessation of life; Clinical; Complex; Country; Cutaneous; Data; Development; Ensure; Environment; Epidermis; Ethics; Event; Extracellular Matrix; Faculty; Family; Family member; Foundations; Funding; Goals; Healed; Health; Hospitalization; Human; Infection; Institution; Knockout Mice; Lead; Leadership; Ligands; Mediator of activation protein; Mentors; Mentorship; Modeling; Molecular; Mus; Operative Surgical Procedures; Pathway interactions; Play; Positioning Attribute; Process; Publishing; Regulation; Research; Research Personnel; Resources; Risk; Role; Scientist; Series; Signal Transduction; Skin; Solutions; Stratification; Surgeon; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; United States; Universities; Wisconsin; Work; Wound Healing; base; career; career development; cell type; clinically relevant; design; directed attention; expectation; healing; improved; in vivo; innovation; insight; keratinocyte differentiation; meetings; monolayer; notch protein; novel; novel strategies; programs; regenerative therapy; skills; therapy development; tissue regeneration; wound

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.

描述（由申请人提供）： 候选人：我的职业目标是成为伤口愈合研究和皮肤伤口再生疗法开发的领导者。为了实现这一目标，我将接受皮肤生物学和缺口信号传导以及研究伦理方面的基础科学方面的强化培训。这将包括正式的课程作业、一对一的指导、在实验室会议、系和大学范围内的研讨会以及全国会议上的演示。我将领导一个新的皮肤生物学研究团队，为了解皮肤伤口愈合机制奠定科学基础。我将在奖励期的第四年之前提交 RO1 申请。最后，我将寻求在国家组织中担任领导职务，以加强该领域的合作努力，并直接关注和资源开发该问题的疗法和解决方案。所有这些步骤将有助于我成功过渡到独立。环境：威斯康星大学是美国首屈一指的研究机构之一，校园内拥有 800 多名生物学家。外科系在联邦资助和外科医生科学家职业发展方面享有全国顶级声誉之一。该部门已调动大量资源，致力于金博士的职业发展，包括启动资金（220,000 美元）和每年 9 个月的受保护时间的保证。此外，金博士还将得到该校区两位杰出科学家和非常成功的导师（艾伦-霍夫曼博士和陈博士）以及其他杰出教师的指导。这些组成部分将为他提供最佳的研究环境，确保他成功过渡到独立。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，专注于开发治疗皮肤伤口的新颖有效的治疗干预措施。本申请的目的是确定 Notch 家族在人类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家族成员通过表皮内增殖、角质形成细胞分化和分层的差异调节在皮肤伤口愈合中发挥重要作用。我们根据我们的初步数据和 Kopan、Dotto、Radtke、Fuchs 等人发表的工作提出了这一假设。拟议的研究计划的基本原理是，它期望对皮肤伤口愈合的分子机制产生新的见解，通过这种机制可以开发出临床相关的治疗干预措施来治疗皮肤伤口，同时为我提供建立独立作为一个人的方法。 临床医生科学家。我们已经做好了开展这些研究的充分准备，因为我们的机构致力于开发伤口愈合的新策略和独立的临床科学家。我创建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 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，K14 特异性 Notch 敲除小鼠中产生的伤口闭合率降低，屏障功能降低。 具体目标#2：描述Notch家族在单层和器官培养模型中皮肤伤口闭合和伤口愈合屏障功能建立中的作用。我们的工作假设是，抑制Notch途径将导致伤口延迟闭合和屏障功能下降，而Notch途径的重新激活将增加闭合率并改善“愈合”的器官型皮肤的屏障功能。 具体目标#3：表征缺口激活的能力 利用嵌合 K14 特异性 Notch1、2 或 3 敲除小鼠治愈体内伤口。我们的工作假设是，激活切口将提高闭合率并改善受伤皮肤的屏障功能。