CAREER: Small Molecule-Mediated Axonal Regeneration

职业：小分子介导的轴突再生

• 批准号: 1151708
• 负责人: Dionicio Siegel
• 金额: $ 50万
• 依托单位: University of Texas at Austin
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1151708&HistoricalAwards=false
• 关键词: CAREER; Small; Molecule; Mediated; Axonal

With this CAREER Award from the Chemistry of Life Processes Program Professor Dionicio Siegel of the University of Texas at Austin will examine new ways to promote axonal regeneration through the use of small molecules. With a set of natural products and analogs that the PI's laboratory has synthesized and demonstrated to possess growth promoting and regenerative activities, both in vitro and in vivo, the molecular events leading to regeneration will be investigated. Due to the challenges of determining the modes of action of small molecules the researchers will use a variety of different methods for target identification including covalent adduct formation (photo-affinity and electrophilic baits) and drug affinity responsive target stability.  These studies will be conducted in combination with APEX mass spectroscopy-based quantitative proteomic analyses. The determination of the mode(s) of action will provide insight into how to control axonal growth and development using small molecules. A second project focused on axonal regeneration will develop laboratory preparations of the natural products xanthofulvin and vinaxanthone.  Both compounds strongly inhibit the inhibitor of axonal regeneration, semaphorin3A.  Xanthofulvin has been studied in vivo in adult rats and leads to remarkable regeneration following complete spinal cord transection. The lack of a laboratory preparation, however, has limited studies to advance the understanding of xanthofulvin's biological effects. The group will test a proposed non-enzymatic dimerization sequence that generates the compounds during fermentation or isolation. The completion of the syntheses will provide a platform for future studies focused on optimizing the biological performance of the compounds.Professor Siegel's freshman research class "Bioprospecting: Isolation of Biologically Active Natural Products from Endophytes" exposes students to a unique combination of botany, ethnobotany, mycology, pharmacology, and organic chemistry providing broad exposure to multiple scientific areas.  In addition, the research is in line with the research group's focus in regeneration and the extracts prepared through this class are screened in the Siegel lab's C. elegans-based neuronal outgrowth assays.  The class utilizes the unique capabilities of the research group, existing collaborations, and the nature conservatory facilities at the Lady Bird Johnson Wildflower Center. Designed by Dr. Siegel to encourage pursuit of careers in the chemical sciences "Texas Shamans" is a program that offers Title I high school students the rare opportunity to participate in genuine research. Seeking to include those currently underrepresented in the sciences, Texas Shamans is aimed specifically at students from low-income families, large concentrations of which are the criterion for Title I designation.  The program studying natural products in native Texas plants has been successfully implemented in ten pilot workshops over the past three years and is being expanded to encompass more Austin area schools and provide a conduit for the placement of students into the research labs of University of Texas at Austin.

得克萨斯大学奥斯汀分校的迪奥尼西奥·西格尔教授获得了生命过程化学项目的职业奖，他将研究通过使用小分子来促进轴突再生的新方法。PI的实验室已经合成了一系列天然产物和类似物，并证明它们在体外和体内都具有促进生长和再生的活性，将研究导致再生的分子事件。由于确定小分子作用模式的挑战，研究人员将使用各种不同的方法进行靶标鉴定，包括共价加合物形成（光亲和和亲电诱饵）和药物亲和反应靶标稳定性。这些研究将结合基于APEX质谱的定量蛋白质组学分析进行。作用模式的确定将为如何使用小分子控制轴突生长和发育提供见解。第二个项目侧重于轴突再生，将开发天然产物黄杂黄素和维纳黄酮的实验室制剂。这两种化合物都能强烈抑制轴突再生抑制剂semaphorin3A。黄嘌呤已在成年大鼠体内进行了研究，并在脊髓完全横断后导致显著的再生。然而，缺乏实验室制备，限制了对黄腐菌素生物学效应的研究。该小组将测试在发酵或分离过程中产生化合物的拟议的非酶二聚化序列。该合成的完成将为未来的研究提供一个平台，重点是优化化合物的生物性能。西格尔教授的大一研究课程“生物勘探：从内生植物中分离出具有生物活性的天然产物”使学生们接触到植物学、民族植物学、真菌学、药理学和有机化学的独特结合，从而广泛接触多个科学领域。此外，该研究符合研究小组对再生的关注，通过该课程制备的提取物在西格尔实验室的秀丽隐杆线虫为基础的神经元生长试验中进行筛选。该课程利用了研究小组的独特能力，现有的合作，以及伯德夫人约翰逊野花中心的自然温室设施。西格尔博士为鼓励人们从事化学科学而设计的“德州萨满”项目为第一名高中学生提供了难得的参与真正研究的机会。为了包括那些目前在科学领域代表性不足的学生，德州萨满专门针对来自低收入家庭的学生，这些家庭的大量集中是第一章指定的标准。在过去的三年里，这个研究德克萨斯本土植物天然产物的项目已经在十个试点车间中成功实施，并正在扩大到更多奥斯汀地区的学校，并为学生进入德克萨斯大学奥斯汀分校的研究实验室提供了一个渠道。