Regulation of Fibroblast Survival in the Collagen Matrix

胶原基质中成纤维细胞存活的调节

• 批准号: 6382569
• 负责人: MARK A CARLSON
• 金额: $ 10.62万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6382569
• 关键词: actins; apoptosis; biological signal transduction; cell growth regulation; collagen; cysteine endopeptidases; enzyme activity; extracellular matrix; fibroblasts; focal adhesion kinase; human tissue; immunocytochemistry; integrins; intermolecular interaction; laboratory mouse; p53 gene /protein; phosphatidylinositol 3 kinase; phosphorylation; protein structure function; skin; terminal nick end labeling; transcription factor; western blottings; wound healing

DESCRIPTION (provided by applicant): The candidate is pursuing a career in academic surgery as an Assistant Professor of Surgery at the University of Nebraska Medical Center. His clinical interests include minimally invasive and robotic surgery and surgery of the abdominal wall His basic science interests include the regulation of wound healing, granulation tissue regression, and tissue regeneration. He has completed a 6 year residency in general surgery (Medical College of Wisconsin), a 1 year fellowship in minimally invasive surgery (MCW), and a 3 year fellowship in basic research (wound healing) with Fred Giinnell at the University of Texas Southwestern Medical Center. His short-term goal is to establish, with the help of extramural funding, a career in academic surgery at UNMC. His long-term goals include a greater understanding of the healing mechanism, progress towards achieving tissue regeneration, and advancement of minimally invasive and robotic surgery. The UNMC Surgery Chairman hired the candidate with the intent that the candidate would concentrate 75 percent of his efforts on research and career development. The candidate?s career development plan involves a combination of basic science research, didactic lectures, seminars, specialty courses, scientific meetings, research presentations, and scholarly debate/discussions. The candidate has 3 sponsors: a senior academic surgeon, a surgeon who is an established wound healing investigator, and a cell biologist experienced in apoptotic signal transduction. The latter two sponsors have NIH-funded laboratories. The candidate foresees a 4 year period to perform the proposed experiments and prepare an R01 application. The candidate's research plan will investigate the regulation of fibroblast survival in the collagen matrix. The clinical relevance is that since the fibroblast is the primary cell involved with complications/untoward effects of healing and scarring, control over fibroblast survival during healing should allow the clinician to minimize the negative effects of scarring in select clinical circumstances, such as in burn wound contracture, GI anastomotic stricture, or cirrhosis. The candidate has hypothesized that matrix anchorage upregulates focal adhesion kinase activity, which in turn upregulates the PI3K/Akt survival pathway and inhibits the tumor suppressor p53, ultimately promoting cell survival. Loss of matrix anchorage is hypothesized to reverse these effects and induce apoptosis. The involvement of each protein will be probed with mutated isoforms.

描述（由申请人提供）： 候选人正在从事以下职业： 学术外科作为外科助理教授在大学 内布拉斯加州医疗中心。他的临床兴趣包括微创和 机器人手术和腹壁手术 他的基础科学兴趣 包括伤口愈合、肉芽组织消退的调节，以及 组织再生。他已完成 6 年普通外科住院医师实习期 （威斯康星医学院），为期 1 年的微创研究金 外科手术（MCW），以及为期 3 年的基础研究（伤口愈合）奖学金 德克萨斯大学西南医学中心的弗雷德·吉内尔 (Fred Giinnell)。他的 短期目标是在外部资金的帮助下建立一个职业生涯 在 UNMC 从事学术外科手术。他的长期目标包括实现更大的目标 了解愈合机制，实现组织的进展 再生以及微创和机器人手术的进步。 UNMC 外科主席聘用该候选人的目的是 候选人将集中 75% 的精力在研究和职业上 发展。候选人的职业发展计划涉及以下方面的组合 基础科学研究、教学讲座、研讨会、专业课程、 科学会议、研究报告和学术辩论/讨论。 候选人有 3 名担保人：一名资深学术外科医生、一名外科医生 建立了伤口愈合研究者和经验丰富的细胞生物学家 凋亡信号转导。后两个赞助商有 NIH 资助 实验室。候选人预计有 4 年时间来执行拟议的 实验并准备 R01 应用程序。 候选人的研究计划将调查成纤维细胞的调节 在胶原蛋白基质中存活。临床相关性在于，由于 成纤维细胞是与并发症/不良影响有关的主要细胞 愈合和疤痕形成，在愈合过程中控制成纤维细胞的存活应该 允许临床医生最大限度地减少选择的疤痕的负面影响 临床情况，如烧伤创面挛缩、胃肠道吻合 狭窄或肝硬化。候选人假设矩阵锚固 上调粘着斑激酶活性，进而上调 PI3K/Akt 生存途径并最终抑制肿瘤抑制因子 p53 促进细胞存活。假设基质锚固的损失会逆转 这些作用并诱导细胞凋亡。每种蛋白质的参与将是 用突变的异构体进行探测。