Procollagen Assembly

原胶原组装

• 批准号: 2236194
• 负责人: Matthew Shoulders
• 金额: $ 97.41万
• 依托单位: Massachusetts Institute of Technology
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2236194&HistoricalAwards=false
• 关键词: Procollagen; Assembly

This project seeks to uncover how collagen, the molecular scaffold for animal life, assembles inside cells into the complex three-dimensional structures required to form skin, bone, cartilage, and other tissues. The advances in fundamental knowledge of collagen biochemistry achieved will have translatable impact, yielding an enhanced ability to create designer biomaterials and an improved understanding of collagen misfolding-related genetic disorders. The research is tightly integrated with continuation and expansion of a successful science outreach program targeting the homeschool community. One arm of the program involves MIT HIP-SAT (Homeschool Internship Program in Science and Technology), a nationally competitive program that brings homeschooled students to leading labs at MIT for funded summer research internships. A second arm of the program targets children in the 8–14 age range, distributing hands-on molecular biology modeling kits that capture students’ attention with chemical concepts that underpin life processes and training the community in effective use of these kits.The fibrillar procollagens are composed of a lengthy, uninterrupted triple-helical domain flanked by a small N-propeptide and somewhat larger globular C-propeptide (C-Pro). The triple helix itself, which is the fundamental structural element of mature collagen, is a trimeric structure in which three distinct, left-handed helical strands wrap around each other to form the right-handed, parallel triple helix. In fibrillar collagens, the most abundant types, these triple helices can span up to ~1000 amino acids in length. These lengthy, repetitive triple-helical domains cannot fold properly on their own. Instead, they require assistance to ensure proper strand selection (some collagens are homotrimeric, while others form 2:1 or even 1:1:1 heterotrimers) and alignment of individual polypeptides. Remarkably, the molecular basis for collagen homo- versus hetero-trimerization is not yet known. This research integrates strategies from synthetic chemistry, biochemistry, structural biology, and cell biology to fill this key knowledge gap. The outcomes will be a new paradigm for understanding collagen assembly mechanisms, as well as a molecular explanation of the complex interplay between thermodynamic and kinetic effects that ensures proper collagen assembly. These results will impact fundamental understanding of the most abundant protein in humans, enable biomaterial applications, and elucidate disease-relevant biology.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.

该项目旨在发现胶原蛋白是如何形成皮肤，骨骼，软骨和其他组织所需的复杂的三维结构的胶原蛋白。实现胶原蛋白生物化学的基本知识的进步将产生可转换的影响，从而增强了创建设计师生物材料的能力，并提高了对胶原蛋白错误折叠相关的遗传疾病的提高。这项研究与针对家庭学校社区的成功科学外展计划的持续和扩展紧密整合在一起。该计划的一个部门涉及MIT HIP-SAT（科学与技术的家庭学校实习计划），这是一个全国竞争性的计划，将家庭学校的学生带到麻省理工学院的领导实验室，以获得资助的夏季研究实习。该计划的第二组针对8-14岁年龄段的儿童，分发了动手的分子生物学建模套件，这些套件可以通过化学概念来吸引学生的注意力，这些化学概念是生命过程和培训社区有效地使用这些套件的。三重螺旋本身是成熟胶原蛋白的基本结构元素，是一种三聚体结构，其中三个不同的，左手的螺旋线相互缠绕，形成右手的平行三重螺旋。在原纤维胶原蛋白中，最丰富的类型，这些三重螺旋的长度最高约为1000个氨基酸。这些长度，重复的三螺旋域不能自行正确折叠。取而代之的是，他们需要协助以确保选择链的适当选择（有些胶原蛋白是同型二元，而另一些胶原蛋白是2：1或什至1：1：1杂三聚体）和单个多肽的对齐。值得注意的是，尚不清楚胶原蛋白均均与异质转化的分子基础。这项研究整合了合成化学，生物化学，结构生物学和细胞生物学的策略，以填补这一关键知识差距。结果将是理解胶原蛋白组装机制的新范式，以及对热力学和动力学效应之间复杂相互作用的分子解释，以确保适当的胶原蛋白组装。这些结果将影响对人类中最丰富蛋白质的基本理解，实现生物材料应用，并阐明与疾病相关的生物学。该奖项反映了NSF的法定任务，并被认为是通过基金会的智力优点和更广泛影响的评估标准通过评估而被视为珍贵的。