BRC-BIO: Interplay Between Intestinal Barrier Function, Aging, and Neurodegeneration

BRC-BIO：肠屏障功能、衰老和神经退行性变之间的相互作用

• 批准号: 2233539
• 负责人: Anna Salazar
• 金额: $ 48.43万
• 依托单位: Christopher Newport University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2233539&HistoricalAwards=false
• 关键词: BRC; BIO; Interplay; Between; Intestinal

The world population is aging, with the number of people over 65 more than doubling to 1.57 billion by 2050, making a concomitant elevation in numerous age-related pathologies, including neurodegenerative diseases such as Alzheimer’s Disease, highly likely. Because of this, a clearer understanding of the pathophysiological changes accompanying aging, and the discovery of novel therapeutics to assist in aging phenotypes, are essential. Recent advances have implicated perturbations in the gut as being closely linked to aging and mortality, with intestinal barrier dysfunction associated with age-related health decline in numerous organisms, including humans. This research will investigate the microbiota-gut-brain axis, the term used to describe communication between commensal bacteria in the gut, gut health, and neurons, to understand if the intestinal barrier dysfunction associated with aging may play a role in the aging pathologies observed in the brain and other tissues, such as muscle. Fundamental details about how communication from the gut may impact aging in tissue outside the gut are poorly understood. Insight into the cellular and molecular changes accompanying the aging gut, how these changes may impact and accelerate aging in the brain and muscle, and whether strengthening the intestinal barrier can reverse or delay aging phenotypes, are, therefore, crucial emerging areas of research. This research will be conducted by a diverse group of undergraduate students, thereby increasing the number of students participating in robust research and gaining experiences leading to more effective scientific communication and the possible pursuit of biological research in future careers. Aging is a process marked by a continuous decline in multiple physiological functions, including the intestinal barrier function, which is tightly linked to longevity in Drosophila melanogaster and other organisms. Previous experiments have revealed that altered expression of occluding junctions in the guts of fruit flies can lead to various hallmarks of aging, including modulation of intestinal homeostasis, variations in microbial dynamics, changes in immune activity, and alterations in lifespan. Loss of a specific occluding junction, Snakeskin (Ssk), leads to rapid and reversible intestinal barrier dysfunction, altered gut morphology, dysbiosis, and a dramatically reduced lifespan. Remarkably, restoration of Ssk expression in flies showing intestinal barrier dysfunction rescues each of these phenotypes previously linked to aging. Intestinal up-regulation of Ssk protects against microbial translocation, improves intestinal barrier function during aging, limits dysbiosis, and extends lifespan. These findings indicate that intestinal occluding junctions may represent prolongevity targets in mammals, in addition to their possible roles in intestinal dysfunction, aging, and disease. This project will investigate the impact of the gut on tissue outside of the gut and address communication between the gut and the brain and muscles in disease models. Current work utilizes cellular and molecular biological methodologies to build upon current knowledge to address crucial questions at the intersection between microbial dysbiosis, epithelial integrity, inflammation, protein aggregation, neurodegeneration, and disease, with the ultimate goal of discovering novel therapies that may enhance barrier function, healthspan, and lifespan.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.

世界人口正在老龄化，到2050年，65岁以上的人口数量将增加一倍以上，达到15.7亿，这使得许多与年龄有关的疾病，包括阿尔茨海默病等神经退行性疾病，很可能随之增加。 正因为如此，更清楚地了解伴随衰老的病理生理变化，并发现新的治疗方法来帮助衰老表型，是必不可少的。 最近的研究进展表明，肠道的扰动与衰老和死亡率密切相关，肠道屏障功能障碍与包括人类在内的许多生物体的年龄相关的健康下降有关。 这项研究将调查微生物群-肠道-脑轴，该术语用于描述肠道中的肠道细菌，肠道健康和神经元之间的通信，以了解与衰老相关的肠道屏障功能障碍是否可能在大脑和其他组织（如肌肉）中观察到的衰老病理学中发挥作用。 关于来自肠道的通信如何影响肠道外组织衰老的基本细节知之甚少。 因此，深入了解衰老肠道伴随的细胞和分子变化，这些变化如何影响和加速大脑和肌肉的衰老，以及加强肠道屏障是否可以逆转或延迟衰老表型，是至关重要的新兴研究领域。 这项研究将由一组不同的本科生进行，从而增加参与强有力的研究和获得经验的学生人数，从而导致更有效的科学交流和在未来的职业生涯中可能追求生物学研究。 衰老是一个以多种生理功能持续下降为特征的过程，包括与果蝇和其他生物体的寿命密切相关的肠道屏障功能。 先前的实验已经揭示，果蝇肠道中闭塞连接的表达改变可以导致衰老的各种标志，包括肠道稳态的调节，微生物动力学的变化，免疫活性的变化和寿命的改变。 一个特定的闭塞连接，蛇皮（Ssk）的损失，导致快速和可逆的肠道屏障功能障碍，改变肠道形态，生态失调，并显着减少寿命。 值得注意的是，在表现出肠屏障功能障碍的果蝇中恢复Ssk表达拯救了先前与衰老相关的这些表型中的每一种。 肠道上调Ssk可防止微生物移位，改善衰老期间的肠道屏障功能，限制生态失调，并延长寿命。 这些发现表明，肠道闭塞连接可能代表哺乳动物的长寿目标，除了它们在肠道功能障碍，衰老和疾病中的可能作用。 该项目将研究肠道对肠道外组织的影响，并解决疾病模型中肠道与大脑和肌肉之间的沟通。 目前的工作利用细胞和分子生物学方法来建立在现有知识的基础上，以解决微生物生态失调，上皮完整性，炎症，蛋白质聚集，神经变性和疾病之间的交叉点的关键问题，最终目标是发现可以增强屏障功能，健康跨度，该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。