CAREER: Small Molecule-Mediated Axonal Regeneration

有了这个职业生涯奖从生命过程的化学计划教授迪奥尼西奥西格尔在奥斯汀得克萨斯大学将研究新的方法来促进轴突再生通过使用小分子。PI实验室合成了一系列天然产物和类似物，并证明其具有体外和体内生长促进和再生活性，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目标识别，包括共价加合物形成（光亲和和亲电子诱饵）和药物亲和响应目标稳定性。 这些研究将结合基于APEX质谱的定量蛋白质组学分析进行。作用模式的确定将提供如何使用小分子控制轴突生长和发育的见解。 第二个项目侧重于轴突再生，将开发天然产品黄霉素和vinaxanthone的实验室制剂。 这两种化合物都强烈抑制轴突再生抑制剂semaphorin3A。 黄霉素已在成年大鼠体内进行了研究，并导致脊髓完全横断后显着再生。然而，由于缺乏实验室制备，限制了对黄霉素生物效应的理解。该小组将测试一个拟议的非酶二聚序列，在发酵或分离过程中产生的化合物。Siegel教授的新生研究课程“生物勘探：从内生菌中分离具有生物活性的天然产物”让学生们了解植物学、民族植物学、真菌学、药理学和有机化学的独特组合，从而广泛接触多个科学领域。 此外，该研究符合研究小组在再生方面的重点，通过这门课制备的提取物在西格尔实验室的C。基于elegans的神经元生长测定。 该课程利用了研究小组的独特能力，现有的合作，以及瓢虫约翰逊野花中心的自然温室设施。 西格尔博士设计的鼓励追求职业生涯的化学科学“得克萨斯州萨满”是一个程序，提供标题一高中学生难得的机会参加真正的研究。寻求包括那些目前在科学中代表性不足，得克萨斯州萨满是专门针对来自低收入家庭的学生，其中大浓度是标题I指定的标准。 在过去的三年里，研究德克萨斯州本土植物中天然产物的计划已经在十个试点讲习班中成功实施，并正在扩大到包括更多的奥斯汀地区学校，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渠道。

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.