Neuronal Mechanisms of Obesity-Induced Hypertension

肥胖症在美国和退伍军人管理局人群中已经很常见，是高血压的主要原因， 是心血管疾病的主要可逆危险因素。然而， 肥胖和高血压之间关系仍不清楚。本提案的目的是确定 控制交感神经活动和血压的神经元和分子过程，以及如何 这些过程中的失调导致肥胖相关的心血管风险。该提案基于 假设下丘脑弓状核神经元中的mTORC 1信号对于 交感神经和血压调节，在肥胖症中具有重要的病理生理意义。我们将 使用多学科策略，结合独特的基因工程小鼠模型， 调制的关键途径，在确定的神经元与新的和尖端的神经技术，以精确 并远程调节自由活动动物中不同弓状核神经元群体的放电， 交感神经和心血管表型的复杂综合生理学。我们将调查 mTORC 1信号在表达阿黑皮素原（POMC）或 刺豚鼠相关蛋白（AgRP）对交感神经活动和动脉压的调节以及肥胖的影响- 相关的高血压和交感神经激活。我们还将使用化学遗传学和光遗传学， 探讨弓状核POMC和AgRP神经元在动脉调节中的功能相关性 正常和肥胖状态下的压力和交感神经活动。这项工作应该能揭示新的机制 这是肥胖相关的交感神经激活和高血压的基础，使我们的工作具有高度的临床意义。 本案无关深入了解控制交感神经张力的细胞和分子过程， 心血管功能可能有可能选择性地干预肥胖造成的损害， 心血管交感神经功能

Obesity which has become common in the US and among the VA population is a major cause of hypertension, a principal reversible risk factor for cardiovascular disease. However, the mechanisms underlying the relationship between obesity and hypertension remain largely unknown. The goal of this proposal is to identify the neuronal and molecular processes that control sympathetic activity and blood pressure and how dysregulation in these processes contribute to obesity-associated cardiovascular risks. This proposal is based on the hypothesis that mTORC1 signaling in the hypothalamic arcuate nucleus neurons are critical for sympathetic and blood pressure regulation with important pathophysiological implications in obesity. We will use a multidisciplinary strategy combining unique genetically engineered mouse models that permit selective modulation of key pathways in defined neurons with novel and cutting edge neuro-technologies to precisely and remotely modulate the firing of distinct arcuate nucleus neuronal populations in freely moving animals with sophisticated integrative physiology for sympathetic and cardiovascular phenotyping. We will investigate the contribution of mTORC1 signaling in arcuate nucleus neurons that express proopiomelanocortin (POMC) or agouti-related protein (AgRP) to the regulation of sympathetic activity and arterial pressure and obesity- associated hypertension and sympathetic nerve activation. We will also use chemogenetic and optogenetics to probe the functional relevance of arcuate nucleus POMC and AgRP neurons for the regulation of arterial pressure and sympathetic activity in normal and obese states. This work should unravel novel mechanisms that underlie obesity-associated sympathetic activation and hypertension, making our work of high clinical relevance. Insights into the cellular and molecular processes that control the sympathetic tone that regulates cardiovascular function may make it possible to selectively interfere with the damage obesity inflicts on cardiovascular sympathetic functions.