Rho-kinase signaling in energy balance

能量平衡中的 Rho 激酶信号传导

• 批准号: 10529777
• 负责人: YOUNG-BUM KIM
• 金额: $ 56.4万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-05 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10529777
• 关键词: Biochemical; Body Weight; Cardiovascular Diseases; Chronic Disease; Data; Desire for food; Eating; Energy Metabolism; Fatty acid glycerol esters; GH1 gene; GTP-Binding Protein alpha Subunits, Gs; Genetic Engineering; Goals; Homeostasis; Human; Hypothalamic structure; Impairment; Lead; Link; MSH receptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Melanocortin 4 Receptor; Metabolic; Metabolic Diseases; Molecular; Morbid Obesity; Mus; Mutant Strains Mice; Mutation; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pakistan; Pathogenesis; Physiological; Population; ROCK1 gene; Recombinant adeno-associated virus (rAAV); Regulation; Rho-associated kinase; Risk Factors; Signal Pathway; Signal Transduction; System; Techniques; Time; Tissue Engineering; Transgenic Mice; Ubiquitination; Variant; Weight Gain; designer receptors exclusively activated by designer drugs; energy balance; experimental study; feeding; insight; mouse model; new therapeutic target; novel; obesity development; obesity treatment

The melanocortin signaling pathway has emerged as a key signaling system regulating normal body-weight homeostasis and energy balance. Activation of melanocortin-4 receptor (MC4R) by -MSH reduces fat stores by decreasing food intake and increasing energy expenditure. Yet, the cellular mechanism(s) underlying melanocortin actions remains poorly understood. Our preliminary data point to the importance of ROCK1 action in MC4R-expressing neurons that is significant for the development of obesity in mice and humans. We found that selective deletion of ROCK1 in MC4R-expressing or Sim1-expressing neurons significantly increases body weight and adiposity. Interestingly, we found that ROCK1 activation in MC4R-containing neurons is required for the anorexigenic action of melanocortin through suppressing AMPK. Evidence demonstrates that UBE2O is an upstream mediator of AMPK that targets 2AMPK for ubiquitination and degradation. Furthermore, we observed that human ROCK1 variant (2824G<A, E942K) from a consanguineous population in Pakistan displays severe obesity, and the mutant mice carrying the human ROCK1 mutation (E942K) are obese. We therefore hypothesize that ROCK1 in MC4R-expressing neurons is necessary for the metabolic regulation of normal body-weight homeostasis and energy balance and is linked with the UBE2O-AMPK signaling cascade for anorexigenic action of melanocortin. Thus, an impaired ROCK1 signaling axis leads to energy imbalance, causing obesity. To this end, we will (i) elucidate the functional importance of ROCK1 in MC4R-expressing neurons in the control of energy balance; (ii) establish the mechanism(s) by which ROCK1 mediates the effect of melanocortin on feeding; and (iii) explore the significance of the human ROCK1 mutation (E942K) in regulating energy balance. To accomplish these goals, we will employ state-of-the-art biochemical, molecular, cellular, and metabolic physiological techniques, including genetically engineered tissue-specific transgenic mouse models, mutant mice carrying the human ROCK1-E942K mutation, Cre-inducible AAV, DREADD, and the rAAV-FlexON switch system. These studies will provide a unique opportunity to establish a novel mechanism implicating ROCK1 as a key determinant of hypothalamic energy balance. The data generated from these timely studies may offer further insights into the pathogenesis of obesity-linked metabolic diseases and lead to new therapeutic targets for the treatment of obesity.

黑色素皮质素信号通路已成为调节正常身体重量的关键信号系统 稳态和能量平衡。 -MSH激活黑色素皮质素-4受体（MC4R） 通过减少食物摄入量并增加能源消耗。然而，基础的细胞机制 黑色皮质素的作用仍然很少理解。我们的初步数据指出了Rock1 Action的重要性 在表达MC4R的神经元中，这对于小鼠和人类肥胖的发展很重要。我们发现 在表达MC4R或表达SIM1的神经元中Rock1的选择性删除可显着增加身体 体重和肥胖。有趣的是，我们发现需要含MC4R的神经元中的Rock1激活 黑色素质素通过抑制AMPK的厌食症作用。证据表明ube2o是 AMPK的上游介体靶向2AMPK用于泛素化和降解。此外，我们观察到 来自巴基斯坦亲属人群的人类Rock1变体（2824g <a，e942k）表现出严重 肥胖和携带人类岩石突变（E942K）的突变小鼠肥胖。因此，我们假设 表达MC4R的神经元中的Rock1对于正常体重的代谢调节是必需的 稳态和能量平衡，并与Ube2O-AMPK信号级联有关，以进行厌食症。 黑色皮质素。这是一个受损的岩石信号传导轴会导致能量失衡，从而导致肥胖。对此 最后，我们将（i）阐明Rock1在表达MC4R神经元中的功能重要性 能量平衡； （ii）建立了Rock1介导黑素皮质素对喂养的作用的机制； （iii）探索人类岩石突变（E942K）在控制能量平衡中的重要性。到 实现这些目标，我们将采用最先进的生化，分子，细胞和代谢 物理技术，包括基因设计的组织特异性转基因小鼠模型，突变体 携带人类岩石1-E942K突变的小鼠，可诱导的AAV，Dreadd和Raav-Flexon开关 系统。这些研究将提供一个独特的机会，以建立一种新颖的机制隐式摇滚1 下丘脑能量平衡的关键决定因素。这些及时研究产生的数据可能会提供 进一步了解与肥胖相关的代谢疾病的发病机理，并导致新的治疗靶标 用于治疗肥胖。