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

由于肥胖的高患病率和与糖尿病的密切联系，肥胖被认为是一个主要的健康问题 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 这种两性异形的原因仍然是难以捉摸的。在我以前的研究中，我首先筛选了体重调节神经元， 研究发现，雌性小鼠的前阿黑皮素（POMC）神经元比雄性小鼠放电更快 POMC神经元和雌性小鼠脑表达更高的POMC转录本。此外，这些性别差异 POMC神经元与TAp 63（一种转录因子）和SRC 1的高表达水平相关 （类固醇受体辅激活因子-1，转录辅激活因子）在女性POMC神经元比男性同行。 初步研究表明，TAp 63可以激活培养细胞中的POMC基因表达。此外，SRC 1 mRNA 在雌性小鼠中，TAp 63缺失显著降低了SRC 1的表达，表明SRC 1是TAp 63的转录靶点。 TAp63.重要的是，小鼠POMC神经元中TAp 63或SRC 1的缺失仅调节小鼠体重。 性二态的时尚总之，我提出了一个假设，雌激素-TAp 63-SRC 1转录 在POMC神经元功能和能量稳态中，轴的性别二型性起作用。我将生成 在POMC神经元中缺乏TAp 63或SRC 1的小鼠，并表征能量稳态和POMC神经元 功能（活性和基因表达谱）在雄性小鼠，雌性小鼠有或没有完整的卵巢（OVX- V）和卵巢不完整但补充雌激素的雌性（OVX-E）。我还会检查雌激素 刺激TAp 63表达和TAp 63是否刺激SRC 1表达。拟议的研究代表 我以前的工作的逻辑扩展，并将推进我们对基础生物学的理解， 体重控制的性别差异，这可能有助于开发性别特异性治疗药物 肥胖和相关代谢疾病的治疗策略。此外，该项目将提供一个理想的培训 我有机会准备一个独立的研究生涯，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.