Retinoic Acid in Male Infertility

 描述(由申请人提供)：本次申请K24职业中期调查员的首要目标是培养有前途的初级调查员，在高质量的以患者为导向的男性生殖研究中。被提名的首席研究员阿莫里博士已经确立了自己作为一名有天赋的研究人员的地位，是初级教职员工和实习生的专职导师。凭借这一奖项，Amory博士希望继续成为男性生殖领域以患者为导向的研究的领导者，并通过亲身实践指导来加强对临床实习生的教育培训，促进他们的个体成长以及男性生殖领域翻译研究的未来。不孕不育影响10 15%的夫妇患有不孕症，而男性伴侣造成的不孕症占所有不孕症病例的30%-40%。最常见的男性不育症包括某些类型的精子发生障碍。不幸的是，大多数患有不孕症的男性没有医学上可以治疗的原因。外科手术精子提取结合体外受精或胞浆内精子注射提供了生育的希望；然而，这些程序是侵入性的，昂贵，在许多情况下不成功，并且不能解决不孕不育的根本原因。因此，需要新的方法来治疗男性不育。在这项申请中提出的工作的目的是获得有助于理解维甲酸在精子发生和男性不育中的作用的知识。在动物模型中，睾丸维甲酸的生物合成是精原细胞分化、精子发生和精子形成所必需的。然而，与实验动物的情况相反，几乎没有研究维甲酸在人类精子发生中的作用。最近，我们的团队发现，精子参数低于正常的男性，睾丸内维A酸水平显著降低，这表明睾丸内维甲酸缺乏可能与男性生精功能受损有关。通过这项资助，我们建议研究睾丸内维甲酸在男性不育症患者中的作用。在这个精液的第一个目标中，我们将通过对男性不育患者接受取精手术的睾丸组织的观察性研究，来研究睾丸内维甲酸与精子发生的关系。在第二个目标中，我们将对精子质量较差的不育男性进行维甲酸治疗的试点临床试验，以确定维甲酸是否能改善射精参数。综上所述，这些实验将极大地提高我们对睾丸内维甲酸与男性精子发生之间关系的理解，并有可能开启治疗男性不育的新的医学途径。

 DESCRIPTION (provided by applicant): The overarching goal of this application for a K24 Midcareer Investigator in Patient-Oriented Research is to foster training of promising junior investigators in high quality patient-oriented research in male reproduction. The proposed principal investigator, Dr. Amory, has established himself as a gifted researcher and is a dedicated mentor to junior faculty and trainees. With this award, Dr. Amory hopes to continue as a leader in patient-oriented research in the area of male reproduction and to enhance the educational training of clinical trainees through hands-on mentorship, facilitating their individua growth as well as the future of translational research in male reproduction. Infertility affects 10 15% of all couples, and infertility attributable to the male partner accounts for 30-40% of all cases of infertility. The most common form of male infertility involves some type of impairment in spermatogenesis. Unfortunately, most men with infertility do not have a medically treatable cause. Surgical sperm extraction coupled with either in vitro fertilization or intra-cytoplasmic sperm injection offers hope of fertility; however, these procedures are invasive, expensive, unsuccessful in many cases, and don't address the underlying cause of infertility. Therefore, new approaches to the treatment of male infertility are needed. The objective of the work proposed in this application is to obtain knowledge useful to understand the role of retinoic acid in spermatogenesis and male infertility. It is well established in animal models that testicular biosynthesis of retinoic acid is required for spermatogonial differentiation, spermiogenesis and spermiation. However, in contrast to the situation in experimental animals, there has been almost no work examining the role of retinoic acid in human spermatogenesis. Recently, our group found that intratesticular retinoic acid is significantly reduced in men who have sub-normal sperm parameters, suggesting that intratesticular retinoic acid deficiency may be related to impaired spermatogenesis in man. With this grant, we propose to examine the role of intratesticular retinoic acid in men presenting with male infertility. In the first aim of this proosal, we will investigate the relationship between intratesticular retinoic acid and spermatogenesis using an observational study in testicular tissue from men undergoing sperm retrieval procedures for infertility treatment. In the second aim, we will conduct a pilot clinical trial of retinoic acid administration to men with infertility from poor sperm quality to determine whether retinoic acid improves ejaculated sperm parameters. Taken together, these experiments will greatly improve our understanding of the relationship between intratesticular retinoic acid and spermatogenesis in man, and have the potential to initiate a novel medical approach to the treatment of male infertility.