Bone and fat: decoding the balancing act of ageing

骨骼和脂肪：解码衰老的平衡行为

• 批准号: RGPIN-2021-03322
• 负责人: Khan, Zia
• 金额: $ 2.04万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=764686
• 关键词: Bone; fat; decoding; balancing; act

Ageing is a complex process that involves every cell in the body and leads to the deterioration of body functions over the lifespan of an individual. Most of this deterioration is linked to our blood vessels. As we age, our tiny blood vessels that supply oxygen and nutrients to our organs, wither and die. This blood vessel damage is responsible for a constellation of human age-related adverse outcomes, such as cardiac and neurologic conditions, muscle loss, and overall frailty. When we are young, aged cells and damaged blood vessels are readily rejuvenated through regeneration. As the regenerative prowess is determined by the ability and potential of our stem cells to replace damaged tissue or aged/worn-out cells, we are as young as our stem cells. Stem cells that are regenerate our blood vessels are mostly found in our long bones. Ageing turns our bones brittle and it takes much longer for bones to heal when fractured. Most importantly, our bones become fatty. The most important fundamental question, therefore, is whether we can restore our blood vessel-forming stem cells if we prevent fatty changes in bones. My research program examines this idea that preserving the integrity of the sites in our body where these stem cells reside will restore their function, effectively `helping the blood vessel repair itself'. To answer the fundamental question posed, I will examine the bones of aged mice and compare the function of blood vessel-forming stem cells to young mice. Next, I will use a cell culture system in which I will grow certain portions of bones in a petri dish to figure out the mechanisms by which fat cells provide harmful signals to the stem cells. I expect that ageing will cause the bones of mice to be fragile and filled with fat, similar to what happens in people over time. I also expect that these changes will cause a drop in the number of blood vessel-forming stem cells. Preventing the bones from fatty changes will prevent bone fragility and restore the number of stem cells to normal levels. I believe that when these mice experience blood vessel damage, their stem cells will be able to combat the changes and repair the damaged vessels. My research will also lead to the discovery of new molecules and processes that keep our stem cells in a stem cell state. My proposed research program will have an impact on several areas. First, understanding of the molecules and processes that enable stem cells to maintain their function and differentiate to rejuvenate damaged blood vessels might be the key to regenerative medicine and an eventual cure for many age-related disorders. Second, my results will provide fundamental knowledge on how bones form, which has implications for osteoporosis. Finally, my studies may generate new knowledge on how to expand stem cells for other stem cell-based applications.

衰老是一个复杂的过程，涉及身体的每一个细胞，并导致身体功能在个人的一生中恶化。这种恶化大部分与我们的血管有关。随着年龄的增长，为我们的器官提供氧气和营养的微小血管会萎缩和死亡。这种血管损伤是造成一系列与人类年龄相关的不良后果的原因，例如心脏和神经系统疾病、肌肉损失和整体虚弱。当我们年轻时，老化的细胞和受损的血管很容易通过再生恢复活力。由于再生能力是由我们的干细胞取代受损组织或老化/磨损细胞的能力和潜力决定的，我们和我们的干细胞一样年轻。 再生我们血管的干细胞主要存在于我们的长骨中。衰老使我们的骨骼变脆，骨折时骨骼需要更长的时间才能愈合。最重要的是，我们的骨骼会变胖。因此，最重要的基本问题是，如果我们防止骨骼中的脂肪变化，我们是否可以恢复血管形成干细胞。我的研究项目检验了这样一个想法，即保持这些干细胞所在的身体部位的完整性将恢复它们的功能，有效地“帮助血管自我修复”。为了回答这个基本问题，我将检查老年小鼠的骨骼，并将血管形成干细胞的功能与年轻小鼠进行比较。接下来，我将使用一个细胞培养系统，在培养皿中培养某些部分的骨骼，以找出脂肪细胞向干细胞提供有害信号的机制。我预计，随着年龄的增长，老鼠的骨骼会变得脆弱，并充满脂肪，就像人类随着时间的推移所发生的情况一样。我还预计这些变化将导致血管形成干细胞数量的下降。防止骨骼发生脂肪变化将防止骨骼脆弱，并将干细胞数量恢复到正常水平。我相信，当这些小鼠经历血管损伤时，它们的干细胞将能够对抗这些变化并修复受损的血管。我的研究还将导致发现新的分子和过程，使我们的干细胞保持在干细胞状态。我提出的研究计划将对几个领域产生影响。首先，了解使干细胞能够维持其功能并分化以恢复受损血管的分子和过程可能是再生医学和最终治愈许多与年龄有关的疾病的关键。其次，我的研究结果将提供有关骨骼如何形成的基础知识，这对骨质疏松症有影响。最后，我的研究可能会产生关于如何为其他基于干细胞的应用扩展干细胞的新知识。