CAREER: Probing the Limits of Affinity and Specificity in Apoptotic Protein Interactions

0952875Link本提案中描述的研究有望在蛋白质工程、蛋白质-蛋白质相互作用和有机化学等领域产生深远影响。预计通过设计Bak多肽的高亲和力变体并在体内测试它们的功能(目标1)，他们将深入了解亲和力在确定细胞死亡中的作用。Bak多肽特异性结合蛋白的分离(Aim 2)是一个具有挑战性的蛋白质工程问题，可以帮助我们深入了解Bclxl和Bcl2在体内的不同功能。最后，使用点击化学稳定螺旋肽的研究是一项创新的跨学科练习，将有机化学技术应用于结构生物学中的一个问题。对凋亡蛋白-蛋白相互作用的研究很重要，因为这些相互作用对细胞死亡以及更广泛的疾病治疗都有影响。高亲和力和高特异性的Bak变异体将在本提案的AIMS 1和2中分离出来，可能作为治疗分子用于癌症的治疗。这项提案的教育部分承诺提高公众对生物技术和生物工程的认识，让更多的学生从很小的年龄开始，一直持续到大学。此外，为了满足和提高学生对生物技术和生物工程的兴趣，还提出了几项本科化学工程教育的改革建议。

0952875LinkThe research described in this proposal promises to have far-reaching impacts in several fields including protein engineering, protein-protein interactions, and organic chemistry. It is expected that by engineering high affinity variants of the Bak peptide and testing their function in vivo (Aim 1) they will gain insights into the role of affinity in the determination of cell death. The isolation of specifically binding Bak peptides (Aim 2) is an intellectually challenging protein engineering problem and may provide insight into the differing functions of Bcl-xL and Bcl-2 in vivo. Finally, the study on using click chemistry to stabilize helical peptides is an innovative cross-disciplinary exercise that brings an organic chemistry technique to bear on a problem in structural biology. The study of apoptotic protein-protein interactions is important because of the impact of these interactions on cell death, and more broadly on the treatment of disease. The high affinity and high specificity Bak variants that will be isolated in Aims 1 and 2 of this proposal may have value as therapeutic molecules for the treatment of cancer. The educational component of this proposal promises to raise public awareness of biotechnology and bioengineering to large groups of students starting at a young age and continuing through college. In addition several innovations in undergraduate chemical engineering education to cater to and enhance student interest in biotechnology and bioengineering are proposed.