Hypothalamic AgRP neurons are determinants of healthy lifespan and higher brain f

描述 摘要： 在晚发性慢性病是具有遗传和表观遗传脆弱性的各种组织长期过度工作的结果这一概念的指导下，我断言，不同组织的细胞能量代谢决定了它们的健康和寿命，从而决定了整个生物体的健康和寿命。基于我以前和正在进行的工作，我假设下丘脑中产生Agouti相关蛋白（AgRP）的一小部分神经元是所有组织能量利用的主要调节器，因此，这些下丘脑神经元决定健康的组织功能和寿命。我们将选择性地上调或下调下丘脑AgRP神经元的活性，并测试这些扰动对外周组织和大脑正常生理的影响。我认为，这些改变周围组织功能的AgRP神经元功能的变化将有关键的影响，以及更高的大脑功能，包括学习和记忆和大脑的能力，以承受压力，在神经退行性疾病诱导的正常老化或病理过程，如阿尔茨海默氏症和帕金森氏症。这个项目是唯一适合NDPA计划，因为它是非常规的，代表了一种方法，在生物医学研究是不存在的。这是一个高风险的途径，但如果成功，将有很大的好处，因为它可以立即导致各种慢性疾病的新疗法。 公共卫生相关性： 迟发性慢性疾病，如痴呆、阿尔茨海默病和帕金森病、糖尿病、心血管疾病和组织恶性肿瘤，是美国发病率和死亡率的主要原因，给个人和社会造成最大的情感和经济负担。随着老龄化人口规模的持续增长，预计迟发性慢性病将进一步主导生物医学和整个社会的关注。该pr

DESCRIPTION Abstract: Guided by the notion that late onset chronic diseases are the consequence of prolonged overworking of various tissues that have genetic and epigenetic vulnerabilities, I assert that it is the cellular energy metabolism of the different tissues that determines their health and longevity and consequently that of the entire organism. Based on my previous and ongoing work, I hypothesize that a small set of neurons in the hypothalamus, which produce Agouti-related protein (AgRP), act as the master regulator of energy utilization by all tissues, and hence, these hypothalamic neurons determine healthy tissue function and longevity. We will selectively up- or down-regulate the activity of hypothalamic AgRP neurons and test the effect of these perturbations on normal physiology of peripheral tissues and that of the brain. I suggest that these changes in peripheral tissue function by altered AgRP neuronal functioning will have critical impact on higher brain functions as well, including learning and memory and the ability of the brain to withstand stress during neurodegeneration induced either by normal aging or by pathological processes, such as Alzheimer's and Parkinson's disease. This project is uniquely suited for the NDPA program because it is unconventional and represents an approach in biomedical research that is nonexistent. It is a high risk avenue, but, if successful, would have great benefits in that it could immediately lead to novel treatments for various chronic diseases. Public Health Relevance: Late onset chronic diseases, such as dementias, Alzheimer's and Parkinson's disease, diabetes, cardiovascular disorders and tissue malignancies, are the leading causes of morbidity and mortality in the U.S., creating the greatest emotional and financial burden on the individual and society. As the size of the aging population continues to grow, late onset chronic diseases are predicted to further dominate the attention of biomedicine and society at large. This pr