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: 6525384
• 负责人: MARK A CARLSON
• 金额: $ 10.39万
• 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/6525384
• 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)：应聘者的职业生涯为 在加州大学担任外科助理教授的学术外科学 内布拉斯加州医疗中心。他的临床兴趣包括微创和 他的基本科学兴趣是机器人外科和腹壁外科 包括对伤口愈合、肉芽组织消退的调节，以及 组织再生。他已经完成了6年的普外科住院医师培训。 (威斯康星医学院)，微创1年奖学金 外科(MCW)，以及三年的基础研究(伤口愈合)研究员 德克萨斯大学西南医学中心的弗雷德·金内尔说。他的 短期目标是在外部资金的帮助下建立一个职业生涯 在大学医学中心做学术外科手术。他的长期目标包括更大的 对愈合机制的理解，实现组织的进展 再生，以及微创手术和机器人手术的发展。 UNMC外科主席聘用候选人的意图是 候选人将把75%的精力集中在研究和职业生涯上 发展。候选人？S的职业发展计划涉及到以下几个方面 基础科学研究，说教讲座，研讨会，专业课程， 科学会议、研究报告和学术辩论/讨论。 候选人有三个赞助人：一名资深学术外科医生，一名外科医生 久负盛名的伤口愈合调查员，以及在 细胞凋亡信号转导。后两个赞助商由美国国立卫生研究院资助 实验室。候选人预计将有4年的时间来执行建议的 实验并准备一个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。临床上的相关性是，由于 成纤维细胞是参与并发症/不良反应的主要细胞。 愈合和疤痕形成，在愈合过程中控制成纤维细胞的存活 允许临床医生最大限度地减少瘢痕形成的负面影响 临床情况，如烧伤创面痉挛、胃肠道吻合 狭窄，或肝硬变。候选人假设母体锚定 上调粘着斑激酶活性，进而上调 PI3K/Akt生存通路并最终抑制肿瘤抑制因子P53 促进细胞存活。假设基质锚定的损失可以逆转 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了探测。