BCL-2 Family Interactions With 2-Trans-Hexadecenal Define Pro-Apoptotic And Anti-Apoptotic Classifications

被感染或突变的细胞通常会通过诱导一种称为细胞凋亡的自杀程序来做出反应。这项计划对健康组织很重要，因为它确保了应激和/或患病的细胞被消除。尽管细胞凋亡在生物学上具有重要意义，但允许细胞自杀的信号还没有完全被理解。该项目的目标是使用最先进的技术组合在单分子水平上了解细胞凋亡，这些技术将揭示基础生物学，并将其应用于生物技术和医学。在整个项目期间，将为高中生、本科生、研究生、研究生和博士后研究员提供研究机会，包括那些在科学和医学方面代表性不足的人，目标是激励和建立一支多样化的科学工作力量。细胞凋亡，或称程序性细胞死亡，在从胚胎形成到癌症形成的生物过程中至关重要。BCL-2(B-cell CLL/Lymphoma 2)家族蛋白是细胞凋亡途径中的重要调节因子，具有促凋亡和抗凋亡的双重功能，因此了解其潜在的作用机制至关重要。BCL-2蛋白如Bax(BCL-2相关的X蛋白，主要促凋亡的BCL-2蛋白)，与其他BCL-2家族蛋白协同作用，导致线粒体膜外膜形成蛋白脂孔。这导致OMM变得可渗透，允许促凋亡蛋白从线粒体中泄漏出来，激活caspase和细胞凋亡。虽然近30年的文献表明，bcl2家族中的蛋白质-蛋白质相互作用从促凋亡功能划分为抗凋亡功能，但新的初步数据显示，脂类结合到促凋亡成员中一个未描述的疏水口袋中是促凋亡功能的真正决定因素。该项目的科学目标是揭示线粒体脂类如何直接改变bax的构象从而导致其激活的详细的基于结构的机制，并通过将脂结合结构域工程到抗凋亡的bcl2蛋白来评估其分子和细胞功能来扩展这些变革性的概念。同时，该项目的一个主要总体目标是通过培养一支拥有方法学技能、分析敏锐性和科学知识的多样化的生物医学研究队伍，培养、激励和促进各级年轻科学家的职业发展。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Cells that become infected or mutated often respond by inducing a suicide program called apoptosis. This program is important to healthy tissues because it ensures that stressed and/or diseased cells are eliminated. Despite the biological importance of apoptosis, the signals that allow for cellular suicide to proceed are incompletely understood. The goal of this project is to understand apoptosis at the single-molecule level using a combination of state-of-the-art techniques that will reveal fundamental biology with applications to biotechnology and medicine. Throughout the duration of this project, research opportunities will be provided to high school students, undergraduate students, post-baccalaureate students, graduate students, and post-doctoral fellows, including those who are underrepresented in science and medicine, with the goal of inspiring and building a diverse scientific workforce.Apoptosis, or programmed cell death, is crucial in biological processes ranging from embryogenesis to carcinogenesis. The BCL-2 (B-cell CLL/Lymphoma 2) family of proteins is a critical regulator in the apoptotic pathway with both pro-apoptotic and anti-apoptotic functions, making it crucial to understand its underlying mechanisms. BCL-2 proteins such as BAX (BCL-2 associated X protein, the major pro-apoptotic BCL-2 protein), collaborate with other BCL-2 family proteins, leading to the creation of proteolipid pores in the outer mitochondrial membrane (OMM). This causes the OMM to become permeable, allowing pro-apoptotic proteins to leak out of the mitochondria to activate caspases and cell apoptosis. While nearly three decades of literature suggest protein-protein interactions within the BCL-2 family delineates anti-apoptotic from pro-apoptotic function, new preliminary data reveal that lipid binding into an uncharacterized hydrophobic pocket in pro-apoptotic members is the true determinant of pro-apoptotic function. The scientific aims of this project are to reveal a detailed structure-based mechanism of how mitochondrial lipids directly alter the conformation of BAX to result in its activation and to expand upon these transformative concepts by engineering lipid-binding domains into anti-apoptotic BCL-2 proteins to evaluate their molecular and cellular functions. In parallel, a major overarching goal of this project is to nurture, inspire, and advance the career development of young scientists at all levels by preparing a diverse biomedical research workforce armed with the methodological skills, analytical acumen, and scientific knowledge.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.