pRb Function in Mediobasal Hypothalamus in Diet Induced Obesity

饮食引起的肥胖中下丘脑内侧基底区的 pRb 功能

基本信息

批准号：
9977171
负责人：
STREAMSON C CHUA
金额：
$ 56.95万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-10 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977171
关键词：
Apoptosis Applications Grants Blood - brain barrier anatomy Blood Circulation Body Weight Brain CDK4 gene Cell Cycle Cell Nucleus Cell Proliferation Cells Cyclin D1 Cyclin-Dependent Kinase Inhibitor 2A Diet Disease Epidemic Equilibrium Etiology Exposure to Fatty acid glycerol esters Functional disorder Gene Expression Genes Health High Fat Diet Homeostasis Hypothalamic structure Impairment Injections Knowledge LEPR gene Leptin Mitotic Modeling Modernization Molecular Mus Mutation Natural regeneration Neurons Obesity POMC gene Pharmacology Phenotype Phosphorylation Play Reducing diet Reproducibility of Results Research Retinoblastoma Protein Role Structure of nucleus infundibularis hypothalami Testing Tumor Suppression Tumor Suppressor Proteins Wild Type Mouse cancer therapy energy balance feeding functional disability improved leptin receptor malignant breast neoplasm median eminence neurogenesis obesity treatment preservation receptor trend tumorigenesis

Apoptosis Applications Grants Blood - brain barrier anatomy Blood Circulation Body Weight Brain CDK4 gene Cell Cycle Cell Nucleus Cell Proliferation Cells Cyclin D1 Cyclin-Dependent Kinase Inhibitor 2A Diet Disease Epidemic Equilibrium Etiology Exposure to Fatty acid glycerol esters Functional disorder Gene Expression Genes Health High Fat Diet Homeostasis Hypothalamic structure Impairment Injections Knowledge LEPR gene Leptin Mitotic Modeling Modernization Molecular Mus Mutation Natural regeneration Neurons Obesity POMC gene Pharmacology Phenotype Phosphorylation Play Reducing diet Reproducibility of Results Research Retinoblastoma Protein Role Structure of nucleus infundibularis hypothalami Testing Tumor Suppression Tumor Suppressor Proteins Wild Type Mouse cancer therapy energy balance feeding functional disability improved leptin receptor malignant breast neoplasm median eminence neurogenesis obesity treatment preservation receptor trend tumorigenesis

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项目摘要

Abstract Obesity is a present and increasing worldwide health threat. The vast majority of obese people contain higher levels of leptin in the circulation, which can be modeled in wild type mice on high fat diet (HFD) to promote diet induced obesity (DIO). Positive energy imbalance in the presence of higher leptin levels indicates reductions in leptin action, which likely contribute to DIO. In this application, we propose to gain better understanding of leptin action reduction in DIO. Major leptin target neurons that regulate energy balance are localized in mediobasal hypothalamus (MBH), which is exposed to the circulation due to the incomplete blood-brain barrier at the Median Eminence. Byproducts in circulation following HFD could therefore impair MBH neuron homeostasis, which we define as a healthy balance of post-mitotic quiescence, proliferation, survival, neurogenesis, and differentiation. The tumor suppressor pRb is a central regulator of cellular homeostasis, we propose to apply the knowledge of pRb function in tumor suppression to study homeostasis of MBH neurons in DIO. We obtained evidence that HFD induces pRb phosphorylation and inactivation in MBH neurons. We then tested the effects of expressing an un-phosphorylable pRb (pRbΔP) in MBH to preserve pRb function in DIO, and found significantly reduced DIO. In this MPI RO1 application, we propose to (1) determine the mechanisms of pRbΔP function in MBH to inhibit DIO, (2) determine the anti-DIO effects of pRbΔP when expressed in POMC neurons, (3) identify non-POMC neurons in MBH that contribute to inhibition of DIO when pRbΔP is expressed in MBH and determine the underlying mechanisms, and (4) determine the translational potential of our finding that expressing pRbΔP in MBH can inhibit DIO.

抽象的肥胖是目前的全球健康威胁。绝大多数肥胖者都包含更高的循环中的瘦素水平，可以在高脂饮食（HFD）上以野生型小鼠进行建模以促进饮食诱发肥胖症（DIO）。在较高的瘦素水平存在下的正能量失衡表明降低在瘦素作用中，可能会导致DIO。在此应用程序中，我们建议更好地了解 DIO的瘦素作用降低。调节能量平衡的主要瘦素靶神经元位于中丘脑下丘脑（MBH），由于不完全的血脑屏障而暴露于循环在中位数。因此，HFD循环中的副产品可能会损害MBH神经元稳态，我们将其定义为有丝分裂后静脉，增殖，生存，生存的健康平衡，神经发生和分化。肿瘤抑制剂PRB是细胞稳态的中心调节剂，我们提出将PRB功能知识应用于肿瘤抑制的知识，以研究MBH神经元的体内稳态 dio。我们获得了HFD诱导PRB磷酸化和MBH神经元失活的证据。然后我们测试了MBH中表达不可磷酸化的PRB（PRBΔP）的影响，以保留DIO中的PRB功能，并发现DIO显着降低了。在此MPI RO1应用中，我们建议（1）确定 PRBΔP在MBH中的机制抑制DIO，（2）确定PRBΔP的抗二氧化碳作用时在POMC神经元中表达，（3）鉴定MBH中的非POMC神经元，这些神经元在MBH中有助于DIO抑制 PRBΔP以MBH表示并确定基本机制，（4）确定翻译我们发现MBH中表达PRBΔP的潜力可以抑制DIO。