Targeting evolutionarily encoded molecular antennae to wirelessly reprogram systemic metabolism

项目摘要/摘要 代谢功能障碍是许多代谢性疾病，包括2型代谢性疾病病因学的中心机制 糖尿病(T2D)。这些扰动是由葡萄糖、脂肪酸和氧化还原的异常重定向驱动的。 代谢途径，有利于脂肪积累和胰岛素抵抗。创新和创新的发展 对这些通路进行精确重新编程的有针对性的策略将成为治疗该病的突破 代谢性疾病。漫长的研究历史表明，所有主要门类的动物都拥有 使生物系统能够感知和响应静态电磁场的未知机制 (电磁场)。在人类中，这种机制无意识地检测到静态电动势和触发器方向的变化 生理变化。如果这些进化上保守的机制能够被利用，它们将导致 自动化、靶向和无药物疗法的发展，精确地重新编程细胞过程 来治疗疾病。然而，一个主要障碍是，这些机制仍然是人们最不了解的机制之一。 在生物学中，我们既不了解它的基本机制，也不了解它的全部生理效应。 电磁场。这项提议的目标是破译一个尚未发现的生物传感器的多细胞网络， 接收和转发电动势信号。我们的目标是利用这些机制来开发新的治疗策略和 使新陈代谢能够无线重新编程的医疗技术。新出现的证据表明 内源性电动势感应机制涉及短暂的、受到严格调控的顺磁自由基，例如 超氧化物。有趣的是，已经提出的促进电动势传感的顺磁自由基 动物也感觉到营养的供应，并与2型糖尿病(T2D)的病理生理学有关。在……里面 在这项建议中，我们将利用我们最近的偶然发现，将糖尿病动物模型暴露于静态 电动势以超氧化物依赖的机制处理T2D，以阐明一个未被发现的电动势网络- 敏感的传感器和代谢途径，可能是无线重新编程新陈代谢的目标。我们的中央 假设微弱的静态电磁场激活了进化上保守的营养感知途径，代表 一种新的生物学基本单位，它将亚原子自旋状态信号传递到全身代谢反应中。 使用最先进的多学科方法探索最深层次的系统新陈代谢 健康和糖尿病状态，我们将破译一种新的内源性信号策略，它接收EMF信号 并将这些信息转化为精确的新陈代谢反应。这项工作将建立一个全面的 静态电磁场影响的代谢图，有可能揭示新的代谢途径， 在没有电动势操纵的情况下仍未被发现。在我们的工作过程中，我们还将确定 地球电磁场对代谢途径的影响。最终，这项提议将为 开发无线精确调整新陈代谢编程的新方法。

Project Summary / Abstract Metabolic dysfunction is a central mechanism in the etiology of numerous metabolic diseases, including type 2 diabetes (T2D). These perturbations are driven by the aberrant redirection of glucose, fatty acid and redox metabolic pathways, favoring fat accumulation and insulin resistance. The development of innovative and targeted strategies to precisely reprogram these pathways would serve as a breakthrough for the treatment of metabolic disease. A long history of work demonstrates that animals across all major phyla possess undiscovered mechanisms that enable biological systems to sense and respond to static electromagnetic fields (EMFs). In humans such mechanisms unconsciously detect changes in the orientation of static EMFs and trigger physiological changes. If these evolutionarily conserved mechanisms could be harnessed, they would lead to the development of automated, targeted and drug-free therapies, which precisely reprogram cellular processes to treat disease. However, a major obstacle is that these mechanisms remain among the least well understood in biology; we understand neither the fundamental mechanisms nor the full range of physiological effects of EMFs. The goal of this proposal is to decipher an undiscovered multicellular network of biological sensors that receive and relay EMF signals. We aim to harness these mechanisms to develop new therapeutic strategies and medical technologies that enable the wireless reprogramming of metabolism. Emerging evidence suggests that endogenous EMF-sensing mechanisms involve short-lived, tightly regulated paramagnetic radicals, such as superoxide. Intriguingly, the paramagnetic radicals which have been proposed to facilitate EMF-sensing in animals, also sense nutrient availability and are implicated in the pathophysiology of type 2 diabetes (T2D). In this proposal, we will leverage our recent serendipitous findings that exposure of diabetic animal models to static EMFs treats T2D in a superoxide-dependent mechanisms to illuminate an undiscovered network of EMF- sensitive sensors and metabolic pathways that may be targeted to wirelessly reprogram metabolism. Our central hypothesis is that weak static EMFs activate an evolutionarily conserved nutrient sensing pathway, representing a novel fundamental unit of biology that relays sub-atomic spin-state signals into systemic metabolic responses. Using state-of-the-art, multidisciplinary approaches to probe the deepest levels of systemic metabolism in healthy and diabetic states, we will decipher a novel endogenous signaling strategy that receives EMF-signals and transmits this information into precise metabolic responses. This work will establish a comprehensive metabolic map of the effects of static EMFs that has the potential to reveal new metabolic pathways, which remain undiscovered in the absence of EMF manipulations. In the process of our work, we will also determine the impact that Earth EMFs have on metabolic pathways. Ultimately, this proposal will pave the way for the development of new approaches which precisely tune metabolic programming, wirelessly.