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: 9342947
• 负责人: Timothy W King
• 金额: $ 19.53万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9342947
• 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; Hospitalization; Human; Infection; Institution; Knockout Mice; Lead; Leadership; Ligands; Mediator of activation protein; Mentors; Mentorship; Modeling; Molecular; Mus; NOTCH3 gene; Operative Surgical Procedures; Pathway interactions; Play; Positioning Attribute; Process; Publishing; Regulation; Research; Research Personnel; Resources; Risk; Role; Scientist; Series; Signal Transduction; Skin; Skin wound; Stratification; Surgeon; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; Treatment Efficacy; 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; public health relevance; regenerative therapy; skills; therapy development; tissue regeneration; wound closure

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，我将接受密集的培训，在基础科学的皮肤生物学和缺口信号，以及道德的研究行为。这将包括正式的课程作业，一对一的指导，在实验室会议，部门和大学范围内的研讨会和国家会议的演示文稿。我将领导一个新生的皮肤生物学研究团队，为理解皮肤伤口愈合机制奠定科学基础。我将提交一个RO 1申请不迟于第4年的奖励期。最后，我将寻求在国家组织中担任领导职务，以加强这一领域的合作努力，并将注意力和资源直接用于开发这一问题的疗法和解决方案。所有这些步骤将有助于我成功地过渡到独立。环境：威斯康星州大学是美国首屈一指的研究机构之一，校园内有800多名生物学家。外科部在联邦资助和外科医生科学家的职业发展方面享有全国最高的声誉。该部调动了大量资源，对金博士的职业发展作出承诺，包括保证提供启动资金（220 000美元）和每年9个月的受保护时间。此外，金博士将由两位杰出的科学家和非常成功的导师在这个校园（艾伦-霍夫曼博士和陈）以及其他优秀的教师指导。这些因素将为他提供一个最佳的研究环境，确保他成功地向独立过渡。调研：我的长期目标是发展一个独立的研究事业，作为一名临床科学家，专注于开发新颖有效的治疗皮肤伤口的治疗干预措施。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的增殖、角质形成细胞分化和分层的差异调节在皮肤伤口愈合中起重要作用。我们基于我们的初步数据和Kopan、Dotto、Radtke、Fuchs等人的已发表工作开发了这一假设。拟议研究计划的基本原理是，它预计将对皮肤伤口愈合的分子机制产生新的见解，通过该机制，可以开发临床相关的治疗干预来治疗皮肤伤口，同时，为我提供了作为一名临床科学家建立独立性的方法。我们已经做好了充分的准备来进行这些研究，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。我已经创建了一个指导团队和合作者，他们拥有指导我追求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Notch 1、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，在K14特异性Notch敲除小鼠中产生的伤口具有降低的闭合率和降低的屏障功能。 具体目标#2：表征Notch家族在皮肤伤口闭合中的作用以及在单层和器官型培养中建模的伤口愈合中屏障功能的建立。我们的工作假设是，切口途径的抑制将导致延迟闭合，并降低伤口中的屏障功能，并且切口途径的重新激活将增加闭合速率并改善“愈合的”器官型皮肤的屏障功能。 具体目标3：表征切口激活的能力， 利用嵌合K14特异性Notch 1、2或3敲除小鼠愈合体内伤口。我们的工作假设是，激活切口将增加闭合率并改善受伤皮肤的屏障功能。