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

• 批准号: 9246962
• 负责人: Stephanie Correa
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-09 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246962
• 关键词: female; specific; neuroendocrine; center; controlling

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：中年女性体重增加通常与更年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有助于开发治疗女性肥胖的新策略。方法：我们开发了一种女性肥胖小鼠模型，其中使用 Sf1 驱动的 CRE 重组酶 Nkx2-1Sf1Cre 小鼠，在下丘脑腹内侧 (VMH) 中转录因子 Nkx2-1 被消除。雌性而非雄性 Nkx2-1Sf1Cre 小鼠肥胖，体力活动减少，VMH 中 ER� 阳性神经元较少。我假设 VMH 中的雌激素反应性 Nkx2-1 神经元调节雌性小鼠的身体活动，而这些神经元的丧失是在 Nkx2-1Sf1Cre 雌性小鼠中观察到的“沙发土豆”表型的基础。为了实现两个目标，我将定义 VMH 中的雌激素反应性 Nkx2-1 神经元如何调节身体活动，并确定它们在移植到肥胖小鼠体内时是否足以挽救久坐行为。影响：Nkx2-1Sf1Cre 小鼠提供了一个独特的机会来定义调节身体活动的性二态性神经内分泌中心。拟议的研究应该为减少女性久坐行为和改善代谢健康提供新的潜在策略。环境：研究导师是发育神经内分泌学领域的领军人物 Holly Ingraham 博士。博士。约翰·鲁宾斯坦 (John Rubenstein)、艾莉森·徐 (Allison Xu) 和艾伦·巴斯鲍姆 (Allan Basbaum) 已同意加入咨询委员会，为职业发展提供专业科学知识和指导。除了研究培训之外，我还建议开设神经科学方面的教学课程和负责任的研究行为。职业目标：我将参加加州大学旧金山分校的职业发展研讨会，为学术研究职业做好准备。总体而言，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研究者做好准备。