EIF4ENIF1

目前全球大约有4800万对夫妻患有不孕不育症，其背后的原因多种多样。在哺乳动物中（包括人类），卵子是在卵巢中产生的，当这一过程出错时就会引起女性不孕，其中一个典型的例子就是卵巢功能不全（premature ovarian insufficiency），其主要表现为女性在40岁前出现卵子相关的问题，目前有高达3.7%的女性都会因为这种状况而遭受不孕，大约30%的病例都是因为遗传突变所引起的。近日，一篇发表在国际杂志Development上题为“Eif4enif1 haploinsufficiency disrupts oocyte mitochondrial dynamics and leads to subfertility”的研究报告中，来自清华大学等机构的科学家们通过研究就识别出了女性不孕症发生的一个关键原因。研究者Kehkooi Kee在该研究领域从事了多年研究，早在2019年他们就在研究过程中遇到了一个患有卵巢功能不全的家庭，即名为Eif4enif1的基因发生的突变似乎是诱发患者卵巢功能不全的原因。于是研究人员决定在小鼠机体中重现这种基因改变来尝试理解Eif4enif1如何影响人类不育，结果发现，这些小鼠机体的卵子会受到线粒体改变的影响，而线粒体则是细胞的能量工厂。随后研究人员利用CRISPR技术在小鼠机体中引入了一种遗传改变，这会促使这些小鼠长大，随后研究人员将其生育能力与机体DNA未经编辑的小鼠的生育能力进行比较，结果发现，在年龄较大且进行过遗传编辑的小鼠中，其机体总卵泡（含有卵细胞的小囊结构）的平均数量下降了大约40%，而且其每窝平均幼崽的数量也会减少33%。重要的是，当在培养皿中培养时，大约一半受精卵都无法存活到发育的早期阶段，这就说明，就好像在人类患者中一样，这些小鼠也经历了不孕的问题。图片来源：https://journals.biologists.com/dev/article-abstract/150/23/dev202151/336522/Eif4enif1-haploinsufficiency-disrupts-oocyte?redirectedFrom=fulltext当研究人员在显微镜下研究来自这些小鼠的卵子时，他们注意到其卵子中的线粒体有些不寻常，线粒体会产生卵细胞所需的能量，其通常会在卵细胞中均匀分布，但发生遗传突变的小鼠机体的卵细胞中的线粒体则会聚集在一起。研究者Kee说道，实际上我们对于线粒体的差异感到非常惊讶，在进行这项研究时，此前我们并未发现Eif4enif1和线粒体之间的关联。这些行为异常的线粒体似乎可能会导致这些小鼠经历不孕的问题，从而就促使研究人员提出，恢复正常的线粒体行为或许就能改善小鼠的不孕问题。本文研究结果为人类不孕不育研究指明了方向，比如确定人类卵巢功能不全患者卵细胞中是否存在线粒体的缺陷，以及当卵细胞受精后胚胎中是否能观察到相同的线粒体缺陷，此外，检测恢复线粒体在卵细胞中的正常分布来改善不孕问题是否能作为一种新型的不孕不育疗法。本文研究表明，挽救卵母细胞中的线粒体异常或许能作为携带遗传突变的不孕症患者的潜在治疗靶点。综上，本文研究结果为临床生育失败背后的分子机制提供了新的见解，也为寻求新型治疗性靶点来开发人类不孕不育的新型疗法奠定了一定的研究基础。原始出处：Yuxi Ding,Zequn He,Yanwei Sha, et al. Eif4enif1 haploinsufficiency disrupts oocyte mitochondrial dynamics and leads to subfertility, Development (2023). DOI:10.1242/dev.202151本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

不孕症影响着全球约4800万对夫妇，导致不孕的原因有很多种。在包括人类在内的哺乳动物中，卵子都是在卵巢中产生的。当这个过程中出现问题，就可能会导致女性不孕，可能遇到的问题包括卵巢早衰。卵巢早衰的特点是在40岁之前出现卵子生成的问题，高达3.7%的女性因为这个原因而不孕，其中约30%的病例是由于基因突变造成的。来自清华大学的颉伟教授主导了一项关于这一主题的新研究，并且从事这项研究多年。“2019年，我们的合作者李教授的团队遇到了一个患有卵巢早衰的患者家庭，我们发现，其病变似乎与一种名为Eif4enif1的基因相关，”颉教授说。图片来源: Pixabay/CC0 Public Domain研究人员决定在小鼠身上重现这种基因变化，以试图了解它是如何影响人类的不孕症的。经过研究发现，这些小鼠的卵子受到其线粒体（细胞的动力源）变化的影响。他们将这一新发现的研究成果发表在《Development》杂志上。研究人员使用CRISPR在小鼠体内引入基因变化。他们让这些老鼠长大，然后将它们的生育功能与DNA未经编辑的老鼠的生育功能进行比较。主导这项研究的第一作者、医学博士/博士研究生Yuxi Ding发现，经过基因编辑的年长小鼠的总卵泡（含有正在发育的小卵泡）的平均数量减少了约40%，每窝幼崽的平均数量减少了33%。他们发现，当在培养皿中培育时，大约有一半的受精卵在发育的早期阶段都无法存活。这表明，就像人类患者一样，这些小鼠也遇到了生育问题。当研究人员在显微镜下研究这些小鼠的卵子时，他们注意到了它们线粒体的异常情况。线粒体产生细胞（包括卵细胞）所需的能量，通常均匀分布在整个卵子中，但具有基因突变的小鼠的卵子中的线粒体却聚集在一起。“我们确实对线粒体的差异感到很惊讶。”颉教授说。“在我们进行这项研究之前，Eif4enif1和线粒体之间的联系从未发现过。”这些行为异常的线粒体很有可能是导致这些小鼠生育问题的原因，因此研究人员提出恢复正常的线粒体行为可能会提高生育能力。这项研究为人类不孕症的未来研究提供了方向，比如确定是否在卵巢早衰患者的卵子中也存在线粒体缺陷，以及在卵子受精后是否观察到相同的线粒体缺陷。此外，测试恢复线粒体的正常分布是否可以提高生育能力有望成为一种新的治疗策略。“我们的研究表明，改变卵母细胞线粒体异常可能成为临床基因突变不孕症患者的潜在治疗目标。”颉教授说。参考文献: Yuxi Ding et al, Eif4enif1 haploinsufficiency disrupts oocyte mitochondrial dynamics and leads to subfertility, Development (2023). DOI: 10.1242/dev.202151责编|探索君排版|探索君End往期精选围观王晓红教授团队：绘制单次冷冻囊胚移植成功的女性植入期外周血microRNA动态表达谱，开拓领域创新研究热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文语言胎教是否有效？研究人员以脑电图监测揭示答案热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~

– New preclinical data show anti-tumor response to Company’s eIF4E inhibitors in ER+ breast cancer – – In vivo proof-of-concept of Ribometrix’s small molecule modulators of RNA biology now demonstrated in additional cancer types with significant unmet need – DURHAM, N.C.--(BUSINESS WIRE)-- Ribometrix, a biotechnology company developing small molecule therapeutics that modulate RNA biology, today presented preclinical data supporting the potential of its eIF4E inhibitors in Estrogen Receptor-positive (ER+) breast cancer at the annual San Antonio Breast Cancer Symposium (SABCS), held December 5-9, 2023, in San Antonio, TX. This builds on analogous data announced last month in melanoma, providing further depth to the data supporting this target and Ribometrix’s portfolio of eIF4E-targeted small molecule inhibitors. Ribometrix’s preclinical studies in ER+ breast cancer include evaluation of eIF4E inhibition via both monotherapy and in combination with standard-of-care (SoC) CDK4/6 inhibitors, which target key pro-oncogenic signaling pathways shared with eIF4E. Furthermore, eIF4E controls parts of the pathway that complement those targeted by CDK4/6 inhibition, suggesting additive benefit from combined therapy. All patients eventually develop resistance to CDK4/6 inhibitors, leaving a large unmet need and opportunity to restore tumor sensitivity to treatment and improve outcomes. Ribometrix expects to present additional data and select a development candidate in 2024. “The data presented at SABCS reflect Ribometrix’s ability to efficiently translate the well-supported eIF4E target hypothesis into an RNA-modulating small molecule drug that has now achieved preclinical in vivo proof-of-concept in an additional tumor indication,” said Michael Solomon, Ph.D., Chief Executive Officer of Ribometrix. “We are encouraged to see the added validation of eIF4E as an important mediator of pro-oncogenic signaling, this time in ER+ breast cancer, and the excellent emerging profiles of our eIF4E inhibitors. These data provide a strong foundation on which to build and refine the clinical development strategy for which eIF4E inhibition can ultimately have the greatest impact for patients.” Key takeaways from the presentation at SABCS include: Daily oral dosing of single agent Ribometrix eIF4E inhibitors shows anti-tumor efficacy in vivo with no signs of overt toxicity in an ER+ breast cancer tumor model Targeting ER+ breast cancer resistant to CDK4/6 inhibitors with a Ribometrix eIF4E inhibitor has the potential to mitigate drug resistance and restore sensitivity to standard of care (SoC) in a second line setting eIF4E inhibition with Ribometrix compounds potentiates cancer cell sensitivity to CDK4/6 inhibition, supporting a combination approach to improve SoC response durability in ER+ breast cancer The data will be presented as a poster by Matthew Friedersdorf, Ph.D. and on display beginning today, December 8, 2023, at 12pm CT, at which time it will become available on the Ribometrix website. About eIF4E Eukaryotic translation initiation factor 4E (eIF4E), the main regulatory component of cap-dependent mRNA translation, selectively promotes pro-oncogenic protein synthesis in response to activation of multiple tumor signaling pathways. Interestingly, many pro-oncogenic signaling pathways require eIF4E activity to promote tumor growth. Clinically, eIF4E activity is elevated in many tumor indications and is typically associated with poor prognosis. Thus, targeting eIF4E has the potential to enhance anti-cancer activity when given in combination with standard-of-care (SoC). Additionally, eIF4E is also central to many resistance mechanisms, therefore eIF4E inhibition has the potential to overcome drug resistance and re-sensitize tumors to anti-cancer therapies. Ribometrix is developing eIF4E inhibitors as a promising therapeutic strategy to inhibit oncogene expression to enhance efficacy in combination with SoC and overcome resistance to targeted anti-cancer therapies. About Ribometrix Ribometrix is a biotechnology company pioneering a completely new class of small molecule therapeutics that modulate RNA biology to treat human diseases. Ribometrix leverages its world-leading expertise in three-dimensional RNA structural analysis to identify novel small molecules that inhibit the production of disease-associated proteins. Ribometrix is advancing multiple internal programs including one targeting the oncogenic RNA-binding protein eIF4E, and has established collaborations with Genentech, a member of the Roche Group, and Vertex Pharmaceuticals, which leverage Ribometrix’s discovery platform. Ribometrix is headquartered in Durham, North Carolina.