The Role of Src-Family Tyrosine Kinases and Srcasm in Ocular Surface Epithelial Wound Repair and Neoplasia

Src 家族酪氨酸激酶和 Srcasm 在眼表上皮伤口修复和肿瘤中的作用

• 批准号: 9539693
• 负责人: Vivian Lee
• 金额: $ 21.14万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9539693
• 关键词: Address; Affect; Area; Award; Biological; Biological Assay; Biology; Blindness; Cataract; Cell Proliferation; Cicatrix; Clinical; Communication; Communities; Conjunctival Neoplasms; Cornea; Corneal Injury; Cutaneous; Data; Dermatology; Development; Development Plans; Diagnosis; Disease; Early Intervention; Early treatment; Educational workshop; Environment; Epithelial; Epithelial Cells; Epithelium; Equipment; Experimental Designs; Eye Development; Eye Neoplasms; Faculty; Funding; Future; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Grant; Growth; Growth and Development function; Human; Immunohistochemistry; In Vitro; Individual; Injury; Institution; Instruction; Investigation; Journals; K-Series Research Career Programs; Knowledge; Laboratories; Lasers; Lead; Leadership; Manuscripts; Mentors; Mentorship; Modeling; Molecular; Molecular Profiling; Mus; Neoplasms; Oncogenic; Ophthalmologist; Ophthalmology; Outcome; Pathologist; Pathway interactions; Pennsylvania; Physicians; Play; Positioning Attribute; Preparation; Process; Property; Publications; Request for Applications; Research; Research Personnel; Resources; Role; SECTM1 gene; Sampling; Schedule; Scientist; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Specimen; Structure; Supervision; Therapeutic; Therapeutic Intervention; Tissues; Training; Transgenic Mice; United States National Institutes of Health; Universities; Vision; Vision research; Visual impairment; Wound Healing; Writing; career; career development; cell motility; conjunctiva; corneal epithelial wound healing; corneal epithelium; design; experience; experimental study; in vivo; in vivo Model; insight; interest; keratinocyte; knock-down; lentiviral-mediated; meetings; member; migration; next generation sequencing; novel; ocular surface; overexpression; prevent; programs; prospective; public health relevance; regenerative; responsible research conduct; skills; small hairpin RNA; src-Family Kinases; targeted treatment; therapeutic development; therapeutic target; transcriptome sequencing; tumor; tumorigenesis; wound

 DESCRIPTION (provided by applicant): This application requests a mentored career development award for an ophthalmology trained ocular pathologist with a scientific interest in understanding key cellular pathways that can be targeted for therapeutic treatment. The candidate will focus initially on the Src-family kinases (SFKs) and Src-activating and signaling molecule (Srcasm) pathway in ocular surface wound healing and tumorigenesis because of prior studies that have shown its significance and amenability for topical therapeutic strategies in skin keratinocyte wounds and tumors. The candidate will have the following objectives during the award period: 1) development of an individual research program through mentorship, didactics, related workshops, and instruction in responsible conduct of research; 2) refinement of research and management skills by way of mentorship and related activities; 3) enhancement of communication and writing skills by means of presentations, manuscript and grant preparations; 4) and acquisition of future funding by assembling preliminary results and designing experimental aims. By the end of the award period, the candidate will have gained the mentorship, knowledge, and valuable hands-on experience required to design, propose and implement experiments in vision research. The candidate's long-term goal is to lead a research program that strategically addresses significant, critical questions in the field of ophthalmic research with novel, rational approaches. This project will be under the supervision of premier, senior investigators from the Department of Ophthalmology and Dermatology, who will jointly provide guidance in the proposed research and candidate's career development. The exceptional scientific environment at the University of Pennsylvania promotes such collaborative efforts between departments. In addition, there is a strong legacy at the University of Pennsylvania of promoting and developing junior faculty members to positions of leadership. The mentors uphold this tradition personally and in their respective departments. Both the Department of Ophthalmology and Dermatology are leading institutions, ranking in the top tier in NIH grant funding, publications in high impact journals, and training of outstanding physicians and scientists. A comprehensive mentoring plan has been created for the progressive growth and development of the candidate's goals and career. The plan includes regular, scheduled meetings between the mentors and candidate; didactics; workshops; and activities to enhance the candidate's research, management, communication, and writing skills. In addition to their guidance, the mentors will provide the necessary resources, equipment, and expertise to execute the specific aims of the proposal. There are multiple cores and institutions throughout the campus, as well, with state-of-the-art equipment that will help facilitate the execution of the proposed aims. The interactive and spirited scientific community that exists at the University of Pennsylvania will provide numerous opportunities for the candidate to promote the results from the K08 award and advance the candidate's career. Vision loss due to ocular surface disease is the second major cause of blindness worldwide. Although the causes are varied, the most common pathway leading to the loss of vision is scarring of the ocular surface. Therapeutic interventions early in the process of wound healing are critical to addressing this global burden. The SFK/Srcasm pathway appears to regulate cellular proliferation, migration, and differentiation in wound healing, making it amenable to therapeutic approaches. This pathway, however, also plays a significant role in tumorigenesis as well, which is expected given the commonalities between wounds and tumors. The results obtained from studying this pathway in both ocular surface wound healing and tumorigenesis, therefore, will lead to potential therapeutic targets in both disorders. This goal will be accomplished with 3 specific aims as listed below. The institution, mentors, and collaborators outlined in this proposal are dedicated to research and cultivating the careers of early investigators. This structured career development plan will position the candidate for independence at the end of the award period. AIM 1) Determine the effect of SFKs on corneal epithelial wound healing. We will determine the effect of Fyn, an SFK member, in in vivo corneal epithelial wound healing using genetically-modified mice; and in in vitro human organotypic corneal wound model using lentiviral knockdown and overexpression of Fyn. AIM 2) Define the effect of Srcasm on corneal epithelial wound healing. We will define the effect of Sracsm in in vivo corneal epithelial wound healing using genetically-modified mice; and in in vitro human organotypic corneal wound model using lentiviral knockdown of Srcasm. AIM 3) Determine the molecular and transcriptional profile of ocular surface squamous neoplasias (OSSN, which are the epithelial tumors of the ocular surface), as well as the effect of SFKs and Srcasm in the development of OSSNs. We will profile conjunctival OSSNs with immunohistochemistry and RNA sequencing; and characterize the effect of lentiviral-mediated Fyn overexpression and Srcasm knockdown in an in vitro conjunctival tumor model.

 描述（由申请人提供）：本申请要求为一位受过眼科培训的眼部病理学家提供指导性职业发展奖，该病理学家对了解可用于治疗的关键细胞途径有科学兴趣。候选人将首先关注 Src 家族激酶（ SFKs）和 Src 激活和信号分子（Srcasm）通路在眼表伤口愈合和肿瘤发生中的作用，因为先前的研究已经表明其对于皮肤局部治疗策略的重要性和适用性候选人在获奖期间将实现以下目标：1）通过指导、教学、相关研讨会和负责任的研究指导来制定个人研究计划；2）通过以下方式完善研究和管理技能；指导和相关活动的方式；3）通过演示、手稿和资助准备来增强沟通和写作技能；4）通过收集初步结果和设计实验目标来获得未来的资金。候选人将获得设计、提出和实施视觉研究实验所需的指导、知识和宝贵的实践经验。候选人的长期目标是领导一个研究项目，战略性地解决视觉领域的重大、关键问题。该项目将在眼科和皮肤科的首席高级研究人员的监督下进行，他们将共同为拟议的研究和候选人的职业发展提供指导。宾夕法尼亚州此外，宾夕法尼亚大学在促进和培养初级教职人员担任领导职务方面有着悠久的传统，导师们在眼科和各自的系中都秉承这一传统。皮肤科是领先的机构，在 NIH 拨款、高影响力期刊上的出版物以及杰出医生和科学家的培训方面均名列前茅，为候选人的目标和职业计划的逐步成长和发展制定了全面的指导计划。包括导师和候选人之间定期举行的会议；以及提高候选人研究、管理、沟通和写作技能的活动。该提案的具体目标在整个校园内设有多个核心和机构，并配备了最先进的设备，这将有助于促进该提案的执行。 宾夕法尼亚大学存在的互动且充满活力的科学界将为候选人提供大量机会来宣传 K08 奖项的成果，并推动候选人的职业生涯。眼表疾病导致的视力丧失是第二个主要原因。尽管导致视力丧失的原因多种多样，但在伤口愈合过程的早期进行治疗干预对于解决这一全球性负担至关重要。调节然而，伤口愈合过程中的细胞增殖、迁移和分化，使其适用于治疗方法，而且考虑到伤口和肿瘤之间的共性，这一点也是预料之中的。因此，眼部伤口表面愈合和肿瘤发生的途径将导致这两种疾病的潜在治疗靶点，该目标将通过以下列出的 3 个具体目标来实现。并培养职业生涯该结构化职业发展计划将使候选人在奖励期结束时获得独立。 AIM 1) 确定 SFK 对角膜上皮伤口愈合的影响 我们将确定 SFK 成员 Fyn 的影响。使用转基因小鼠进行体内角膜上皮伤口愈合；以及使用慢病毒敲低和过表达 AIM 进行体外人器官角膜伤口模型 2) 定义 AIM 的作用。 Srcasm 对角膜上皮伤口愈合的影响。我们将使用转基因小鼠来确定 Sracsm 在体内角膜上皮伤口愈合中的作用；并使用 Srcasm 的慢病毒敲低来确定 Srcasm 的分子和转录谱。眼表鳞状细胞瘤（OSSN，眼表上皮性肿瘤）的发病机制及其效果我们将通过免疫组织化学和 RNA 测序来分析 SFK 和 Srcasm 在 OSSN 发展中的作用；并表征慢病毒介导的 Fyn 过表达和 Srcasm 敲低在体外结膜肿瘤模型中的作用。