Sex Differences in Stress Receptors Underlie Female Vulnerability to Stress

与压力相关的精神障碍，如抑郁症和创伤后应激障碍，正在使人虚弱 精神疾病影响的女性人数是男性的两倍。尽管这种差异的原因仍然是 尚不清楚，这被认为是由于性别在压力反应上的差异。促肾上腺皮质激素释放因子 协调应激反应，部分是通过调节去甲肾上腺素(NE)和5-羟色胺(5-HT)的传递， CRF在应激相关的疾病中调节失调。我目前研究的目标是辨别性别 CRF受体(CRF1亚型)的差异可能解释了应激反应的性别差异。 到目前为止，我发现CRF1在雌性大鼠身上的信号和被贩卖的方式不同，这可以解释 对急性应激的反应增强，对慢性应激的适应性降低。在女性中，CRF1 免疫沉淀显示了与Gs的更强偶联，Gs是介导大多数细胞的GTP结合蛋白 回应。此外，应激诱导的CRF1与受体中的一个不可或缺的步骤？-arrestin2相关 内化在男性身上很明显，但在女性身上不明显。免疫电子显微镜证实应激诱导 CRF1仅在雄性大鼠体内内化，表明这种适应过程能够大量代偿 在抑郁症中可能释放的CRF在女性中受到损害。重要的是，CRF1的性别差异 功能使雌性大鼠蓝斑去甲肾上腺素神经元对低水平的CRF和 不太适应高水平的慢性肾功能衰竭。然而，由于这是关于压力性别差异的第一份报告- 与神经肽受体相关的许多问题仍未得到解答。本提案的目标1，这将是 在指导阶段(K99)完成，调查为什么CRF1在男性和 女性。CRF1的结构没有性别差异，所以我将学习蛋白质组学的方法来鉴定 CRF1翻译后修饰的性别差异是否解释了这些影响。目标2和目标3将 在独立阶段完成。目标2将确定有助于性行为的荷尔蒙 CRF1的差异。为此，我将把以前学到的内分泌技术与学到的技能结合起来 在K99期，以确定卵巢或睾丸激素是否建立性别差异。目标3 将评估性别差异是否延伸到中缝背核的另一种受体亚型CRF2。 由于CRF1和CRF2具有高度的序列同源性，蛋白质组学方法有望 揭示CRF2的性别差异。CRF2激活背侧中缝-5-羟色胺系统促进被动 对压力的行为反应策略是抑郁的一个危险因素。因此，CRF2的性别差异可能 导致女性患这种疾病的脆弱性增加。通过解决这些问题，这项提案 将有助于阐明应激相关障碍中性别差异的病因。此外，由于CRF 正在开发拮抗剂来治疗这些疾病，考虑到CRF受体的性别差异可能 提高这些化合物对女性的疗效。

Stress-related psychiatric disorders, like depression and post-traumatic stress disorder, are debilitating mental illnesses that affect twice as many women as men. Although the etiology of this disparity remains unknown, it is thought to be due to sex differences in stress responses. Corticotropin-releasing factor (CRF) orchestrates stress responses, in part, by regulating norepinephrine (NE) and serotonin (5-HT) transmission, and CRF is dysregulated in stress-related disorders. The goal of my current research is to identify sex differences in a receptor for CRF (CRF1 subtype) that may account for sex differences in stress responsivity. To date, I found that CRF1 signals and is trafficked differently in female rats in a manner that can account for elevated responses to acute stress and decreased adaptation to chronic stress. In females, CRF1 immunoprecipitation revealed a greater coupling to Gs, the GTP-binding protein that mediates most cellular responses. Additionally, stress-induced CRF1 association with ¿-arrestin2, an integral step in receptor internalization, was apparent in males but not females. Immunoelectron microscopy confirmed stress-induced CRF1 internalization in male rats only, suggesting that this adaptive process to compensate for large amounts of CRF, as may be released in depression, is compromised in females. Importantly, sex differences in CRF1 function rendered NE neurons in the locus coeruleus of female rats more sensitive to low levels of CRF and less adaptable to high levels of CRF. However, because this is the first report of sex differences in stress- related neuropeptide receptor, many questions remain unanswered. Aim 1 of this proposal, which will be completed during the mentored phase (K99), investigates why CRF1 binds proteins differently in males vs. females. There are no sex differences in CRF1 structure, so I will learn proteomic approaches to identify whether sex differences in post-translational modifications of CRF1 account for these effects. Aims 2 and 3 will be completed during the independent phase. Aim 2 will identify the hormones that contribute to the sex difference in CRF1. To this end, I will combine previously acquired endocrine techniques with the skills learned during the K99 phase to determine whether ovarian or testicular hormones establish the sex differences. Aim 3 will evaluate whether sex differences extend to the other receptor subtype, CRF2, in the dorsal raphe nucleus. Because CRF1 and CRF2 share a high degree of sequence identity, proteomic approaches are expected to reveal sex differences in the CRF2. CRF2 activation of the dorsal raphe-5-HT system promotes a passive behavioral response strategy to stress that is a risk factor for depression. Thus, sex differences in CRF2 may contribute to the increased vulnerability of females this disorder. By addressing these questions, this proposal will help elucidate the etiology of sex differences in stress-related disorders. Moreover, because CRF antagonists are being developed to treat these illnesses, considering sex differences in CRF receptors may increase the efficacy of these compounds in women.