A TAP63 TRANSCRIPTIONAL AXIS CONTRIBUTES TO THE SEXUAL DIMORPHISM IN POMC NEURON FUNCTIONS AND ENERGY HOMEOSTASIS

肥胖被认为是一个主要的健康问题，因为它的患病率很高并且与糖尿病密切相关 和其他代谢紊乱。雌性动物比雄性动物更能抵抗肥胖，但其机制 因为这种性别二态性仍然难以捉摸。在我之前的研究中，我首先筛选了体重调节神经 群体，发现雌性小鼠的阿片黑皮质素原 (POMC) 神经元比雄性小鼠放电更快 POMC 神经元和雌性小鼠大脑表达更高的 POMC 转录本。此外，这些性别差异 POMC 神经元与 TAp63（转录因子）和 SRC1 的较高表达水平相关 （类固醇受体辅激活因子-1，一种转录辅激活因子）在女性 POMC 神经元中的含量高于男性。 初步研究表明，TAp63 可以激活培养细胞中的 POMC 基因表达。此外，SRC1 mRNA 在雌性小鼠中，TAp63 缺失显着降低，表明 SRC1 是 TAp63。重要的是，仅在小鼠 POMC 神经元中删除 TAp63 或 SRC1 可以调节体重 性别二态时尚。我共同提出了一个假设：雌激素-TAp63-SRC1 转录 轴有助于 POMC 神经元功能和能量稳态的性别二态性。我将生成 POMC 神经元中缺乏 TAp63 或 SRC1 的小鼠，并表征能量稳态和 POMC 神经元 雄性小鼠、有或没有完整卵巢的雌性小鼠（OVX- V)，以及没有完整卵巢但补充雌激素的女性 (OVX-E)。我也会检查是否有雌激素 刺激 TAp63 表达以及 TAp63 是否刺激 SRC1 表达。拟议的研究代表 对我之前的工作进行了逻辑扩展，并将增进我们对基础生物学的理解 体重控制方面的性别差异，这可能有助于开发针对性别的治疗方法 肥胖和相关代谢疾病的策略。此外，该项目还将提供理想的培训 有机会为我的独立研究生涯做好准备，专注于转录机制 下丘脑及其在代谢控制中的作用。

Obesity is recognized as a major health issue due to its high prevalence and strong association with diabetes and other metabolic disorders. Female animals are more resistant to obesity than males, but the mechanisms for this sexual dimorphism remain elusive. In my previous studies, I first screened body weight-regulatory neural populations and found that pro-opiomelanocortin (POMC) neurons in female mice fire more rapidly than male POMC neurons, and female mouse brains express higher POMC transcripts. Further, these sex differences in POMC neurons were associated with higher expression levels of TAp63 (a transcription factor) and SRC1 (steroid receptor coactivator-1, a transcriptional coactivator) in female POMC neurons than in male counterparts. Pilot studies showed that TAp63 can activate POMC gene expression in cultured cells. Further, SRC1 mRNA was significantly reduced by TAp63 deletion in female mice, suggesting that SRC1 is a transcription target of TAp63. Importantly, deletion of TAp63 or SRC1 only in POMC neurons in mice regulates body weight in a sexually dimorphic fashion. Together, I developed a hypothesis that an estrogen-TAp63-SRC1 transcriptional axis contributes to the sexual dimorphism in POMC neuron functions and energy homeostasis. I will generate mice that lack TAp63 or SRC1 in POMC neurons, and characterize energy homeostasis and POMC neuron functions (activity and gene expression profile) among male mice, female mice with or without intact ovary (OVX- V), and female without intact ovary but with estrogen supplement (OVX-E). I will also examine whether estrogen stimulates TAp63 expression and whether TAp63 stimulates SRC1 expression. The proposed studies represent logical extensions to my previous work, and will advance our understanding about the fundamental biology for sex differences in body weight control, which may facilitate the development of gender-specific therapeutic strategies for obesity and associated metabolic diseases. In addition, this project will provide an ideal training opportunity to prepare me for an independent research career focusing on transcriptional mechanisms in the hypothalamus and their roles in metabolic control.