MICA Pharmacological, molecular and cellular mechanisms of muscarinic slowing (modification) of neurodegenerative disease.

痴呆症是目前全球面临的主要卫生挑战之一。仅在欧洲，预计到2030年，由神经退行性疾病（如阿尔茨海默病）引起的痴呆症将增加到1400万，这一趋势将使痴呆症成为第一世界仅次于癌症的第二大发病原因(1)。然而，痴呆症并不局限于世界上最富裕的国家。老年人口增长最快的将是发展中国家，包括中国、印度以及南亚和西太平洋国家，这些国家的老年人口增长最快。与疟疾、艾滋病毒和结核病等许多其他全球卫生挑战不同，目前尚无减缓或预防神经退行性疾病进展的治疗方法。此外，正在开发和正在进行临床试验的药物数量少得惊人。因此，全球迫切需要开发减缓或预防神经退行性疾病进展的新药。这项拨款直接解决了这个问题。我们发现，通过激活一种特定的大脑蛋白质，我们可以减缓老鼠神经退行性疾病的进展。这种疾病被称为鼠（鼠）朊病毒病，与人类克雅氏病（又称CJD和疯牛病）相似。我们已经发现，结合并激活一种叫做M1毒蕈碱乙酰胆碱受体的蛋白质的药物类分子可以减缓老鼠体内朊病毒疾病的进展，从而延长它们的寿命。这项拨款旨在确定这种受体蛋白的激活如何延缓疾病进展，以及如何最好地设计药物来激活这种受体蛋白。然后，我们将测试我们发现的减缓朊病毒疾病的药物是否也能减缓其他类型的神经退行性疾病，包括阿尔茨海默病。通过这种方式，这笔拨款将确立可用于制造减缓甚至阻止人类神经退行性疾病的药物的原则。

Dementia is currently one of the major global health challenges. In Europe alone, dementia resulting from neurodegenerative diseases, such as Alzheimer's disease, is projected to rise to 14 million by 2030 - a trajectory that will make dementia second only to cancer as a cause of morbidity in the first world (1). Dementia is not, however, limited to the world's wealthiest countries. The most dramatic increases will be in developing countries including China, India and countries in South Asia and the Western Pacific, where there is the fastest growth in the elderly population. Unlike many other global health challenges, such as malaria, HIV and TB, there are currently no treatments available that slow or prevent the progression of neurodegenerative disease. Furthermore, the pipeline of drugs in development and undergoing clinical testing are alarmingly small. There is therefore an urgent global need to develop new drugs that slow or prevent the progression of neurodegenerative disease. This grant directly addresses this question. We have found that by activating a specific brain protein we can slow the progression of a neurodegenerative disease in mice. This disease is called murine (mouse) prion disease and is similar to human Creutzfeldt-Jakob disease otherwise called CJD and mad cow disease. We have discovered that drug like molecules that bind to and activate a protein called the M1 muscarinic acetylcholine receptor can slow the progression of prion disease in mice, thereby extending their life. This grant is aimed at determining how the activation of this receptor protein can slow disease progression and how best to design drugs to activate this receptor protein. We will then test if the ability of the drugs we discover to slow prion disease can also slow other types of neurodegenerative disease, including Alzheimer's disease. In this way this grant will establish the principles that can be employed to make drugs that slow or even stop neurodegenerative diseases in people.