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A female-specific neuroendocrine center controlling energy expenditure

女性特有的神经内分泌中心控制能量消耗

基本信息

批准号：
8731881
负责人：
Stephanie Correa
金额：
$ 12.42万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-09 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8731881
关键词：
Adult Advisory Committees Affect Behavior Body Weight Brain region Cell Nucleus Complex Data Designer Drugs Development Diet Educational workshop Energy Metabolism Engineering Enterobacteria phage P1 Cre recombinase Environment Estrogen Receptor alpha Estrogen Therapy Estrogens Exhibits Fatty acid glycerol esters Female Fertility Fetus Funding Genetic Recombination Goals Health Holly Hormonal Hormone replacement therapy Hormones Hypothalamic structure Label Lead Leptin Mediating Menopause Mentors Metabolic Modeling Molecular Mus Neuroendocrinology Neurokinin A Neurons Neuropeptides Neurosciences Neurosecretory Systems Obese Mice Obesity Phenotype Physical activity Play Population Postmenopause Potato Reporter Research Research Personnel Research Training Risk Rodent Role Signal Transduction Stroke Substance P Therapeutic Training Activity Transplantation Visceral Weight Gain Woman Women&apos s Health career career development energy balance improved male malignant breast neoplasm middle age mouse model mutant neural circuit neuron loss novel novel strategies public health relevance receptor reproductive research and development responsible research conduct sedentary transcription factor ventromedial hypothalamic nucleus

项目摘要

DESCRIPTION (provided by applicant):Rationale: Weight gain in middle-aged women often is associated with declining estrogen at the onset of menopause. Hormone replacement therapy (HRT) can curb postmenopausal weight gain but can also increase the risk of stroke and breast cancer. Understanding how estrogen-responsive neurons regulate physical activity and energy expenditure may lead to the development of novel strategies for treating obesity in women. Approach: We have developed a mouse model of female obesity in which the transcription factor Nkx2-1 is ablated in the ventromedial hypothalamus (VMH) using Sf1-driven CRE recombinase, Nkx2- 1Sf1Cre mice. Female but not male Nkx2-1Sf1Cre mice are obese and exhibit reduced physical activity and fewer ER¿-positive neurons in the VMH. I hypothesize that estrogen-responsive Nkx2-1 neurons in the VMH regulate physical activity in female mice and that loss of these neurons underlies the "couch-potato" phenotype observed in Nkx2-1Sf1Cre females. In two aims, I will define how estrogen-responsive Nkx2-1 neurons in the VMH regulate physical activity and determine if they are sufficient to rescue sedentary behavior when transplanted into obese mice. Impact: Nkx2-1Sf1Cre mice offer a unique opportunity to define a sexually dimorphic neuroendocrine center that regulates physical activity. The proposed studies should provide new potential strategies for decreasing sedentary behavior and improving metabolic health in women. Environment: The research mentor is Dr. Holly Ingraham, a leader in the field of developmental neuroendocrinology. Drs. John Rubenstein, Allison Xu, and Allan Basbaum have agreed to serve on an Advisory Committee to provide specialized scientific expertise and guidance in career development. In addition to research training, I propose didactic coursework in neuroscience and the responsible conduct of research. Career goals: I will participate in career development workshops at UCSF to prepare for a career in academic research. Overall, the proposed research and career development training activities will prepare me to become an independent investigator in the field of obesity research.

描述（由申请人提供）：理由：中年妇女体重增加通常与绝经期开始时雌激素下降有关。激素替代疗法（HRT）可以抑制绝经后体重增加，但也会增加中风和乳腺癌的风险。了解雌激素反应神经元如何调节身体活动和能量消耗可能会导致治疗女性肥胖症的新策略的发展。方法：我们已经开发了一种雌性肥胖小鼠模型，其中使用Sf 1驱动的CRE重组酶在腹内侧下丘脑（VMH）中消融转录因子Nkx 2 -1，Nkx 2 - 1 Sf 1Cre小鼠。雌性而非雄性Nkx 2 - 1 Sf 1Cre小鼠肥胖，表现出身体活动减少和VMH中ER？阳性神经元减少。我假设，雌激素反应Nkx 2 -1神经元的VMH调节雌性小鼠的身体活动，这些神经元的损失的基础上观察到的“沙发土豆”表型Nkx 2 - 1 Sf 1Cre女性。在两个目标中，我将定义VMH中的雌激素反应性Nkx 2 -1神经元如何调节身体活动，并确定它们是否足以在移植到肥胖小鼠时挽救久坐行为。影响：Nkx 2 - 1 Sf 1Cre小鼠提供了一个独特的机会来定义一个调节身体活动的性二态神经内分泌中心。拟议的研究应该为减少久坐行为和改善女性代谢健康提供新的潜在策略。环境：研究导师是冬青博士英格拉哈姆，在发育神经内分泌学领域的领导者。John Rubenstein博士、Allison Xu博士和Allan Basbaum博士已同意加入咨询委员会，为职业发展提供专业的科学知识和指导。除了研究培训，我建议在神经科学和负责任的研究行为的教学课程。职业目标：我将参加在加州大学旧金山分校的职业发展研讨会，为学术研究的职业生涯做准备。总的来说，拟议的研究和职业发展培训活动将使我成为肥胖研究领域的独立调查员。