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

BCL-2 家族与 2-反式十六烯醛的相互作用定义了促凋亡和抗凋亡分类

• 批准号: 2217138
• 负责人: Jerry Chipuk
• 金额: $ 113.2万
• 依托单位: Icahn School of Medicine at Mount Sinai
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2217138&HistoricalAwards=false
• 关键词: BCL; Family; Interactions; Trans; Hexadecenal

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.

被感染或突变的细胞通常通过诱导称为凋亡的自杀程序来做出反应。这个程序对健康组织很重要，因为它确保了压力和/或患病细胞被消除。尽管细胞凋亡的生物学重要性，允许细胞自杀进行的信号不完全理解。该项目的目标是使用最先进的技术组合来了解单分子水平的细胞凋亡，这些技术将揭示基础生物学与生物技术和医学的应用。在本项目期间，将为高中生、本科生、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领域代表性不足的人，目的是激发和建立多样化的科学人才队伍。细胞凋亡或程序性细胞死亡在从胚胎发生到癌症发生的生物过程中至关重要。BCL-2（B细胞CLL/淋巴瘤2）蛋白家族是具有促凋亡和抗凋亡功能的凋亡途径中的关键调节剂，这使得理解其潜在机制至关重要。BCL-2蛋白如BAX（BCL-2相关X蛋白，主要的促凋亡BCL-2蛋白）与其他BCL-2家族蛋白协作，导致在线粒体外膜（OMM）中产生蛋白脂质孔。这导致OMM变得可渗透，允许促凋亡蛋白从线粒体中漏出以激活半胱天冬酶和细胞凋亡。虽然近三十年的文献表明BCL-2家族内的蛋白质-蛋白质相互作用从促凋亡功能中描绘出抗凋亡功能，但新的初步数据显示，脂质结合到促凋亡成员中的未表征的疏水口袋中是促凋亡功能的真正决定因素。该项目的科学目的是揭示线粒体脂质如何直接改变BAX构象以导致其激活的详细结构机制，并通过将脂质结合结构域工程化到抗凋亡BCL-2蛋白中来扩展这些变革性概念，以评估其分子和细胞功能。与此同时，该项目的一个主要总体目标是培养、激励和促进各级年轻科学家的职业发展，培养一支具备方法技能、分析能力和科学知识的多样化生物医学研究队伍。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。