MRC Transition Support Award [CDA] [Maria Jimenez-Sanchez]

传统上，药物发现策略将神经元作为阿尔茨海默病和其他大脑疾病的主要靶点。在大脑中，神经元负责处理信息、学习和记忆，而其他被称为神经胶质细胞的专门脑细胞是维持神经元健康和帮助其功能所必需的。为了设计有效的阿尔茨海默病治疗策略，我们不仅需要研究神经元如何变得功能失调，而且我们还需要更好地了解神经胶质细胞在疾病进展中的作用。我的职业发展奖的目的是研究星形胶质细胞--最丰富的胶质细胞类型--如何保护阿尔茨海默病中的神经元。我们计划确定星形胶质细胞释放的一些调节神经保护的因子，有了这些信息，我们将能够设计新的有效的治疗方法。我们目前的研究导致了新的和令人兴奋的发现，确定了暴露在与阿尔茨海默病大脑相似的条件下的星形胶质细胞释放的因子。这些因素被称为伴侣蛋白，它们有助于防止异常蛋白质在大脑中积累。更有趣的是，神经元可以吸收星形胶质细胞释放的伴侣，可能是为了保护神经元。这个过渡支持奖将使我的团队能够扩大我们令人兴奋的发现，并探索模仿星形胶质细胞释放伴侣的潜在神经保护作用。在阿尔茨海默病中，tau蛋白在神经元内积聚并形成团块。这项建议将探索增加星形胶质细胞释放因子作为预防tau凝块形成的潜在疗法的潜在好处。我们将通过将伴侣蛋白输送到小鼠脑片中来做到这一点，在其中我们将促进tau的积累，以模拟阿尔茨海默病的大脑。为了进一步确保我们的发现与人类疾病相关，我们将在阿尔茨海默病患者捐赠的死后大脑细胞外空间以及阿尔茨海默病患者的脑脊液中检测这些伴侣蛋白。我是一名痴呆症研究人员，致力于建立和巩固我作为独立小组组长的职业生涯。这一奖项将使我能够扩展我的新研究途径，我的发现将对我们对阿尔茨海默病和相关疾病的理解产生重大影响，并为治疗提供新的方向。

Drug discovery strategies have traditionally focused on neurons as the main targets in Alzheimer's disease and other brain disorders. In the brain, neurons are responsible for processing information, learning and memory, while other specialised brain cells called glial cells are necessary to maintain neuron health and to aid their function. To design effective therapeutic strategies for Alzheimer's disease, not only do we need to investigate how neurons become dysfunctional but also we need to better understand the contribution of glial cells to disease progression. The aim of my Career Development Award is to investigate how astrocytes, the most abundant type of glial cell, can protect neurons in Alzheimer's disease. We plan to identify some of the factors released from astrocytes that mediate neuroprotection, and with this information we will be able to design new and effective therapies. Our current research has led to novel and exciting discoveries that identified factors released from astrocytes exposed to conditions similar to those in Alzheimer's disease brain. These factors are known as chaperones, and they help to prevent the accumulation of abnormal proteins in the brain. What is even more interesting is that neurons can take up the chaperones released by astrocytes, perhaps in an attempt to protect the neurons.This Transition Support Award will enable my group to expand on our exciting findings and explore the potential neuroprotective effects of mimicking chaperone release from astrocytes. In Alzheimer's disease, tau protein builds up and forms clumps inside neurons. This proposal will explore the potential benefits of increasing astrocyte-released factors as a potential therapy to prevent tau clumps from forming. We will do this by delivering chaperones to slices of mouse brain, in which we will promote tau accumulation to mimic Alzheimer's disease brain. To further ensure that our findings are relevant to human disease, we will examine these chaperones in the spaces outside cells in post-mortem brain donated by people with Alzheimer's disease, as well as in cerebrospinal fluid from people living with Alzheimer's disease. I am a dementia researcher who is dedicated to building and consolidating my career as an independent group leader. This Award will enable me to expand my novel avenue of research and my findings will have a significant impact on our understanding of Alzheimer's disease and related disorders, as well as providing new directions for therapies.