COOPERATIVE MULTICENTER REPRODUCTIVE MEDICINE NETWORK

我们的总体目标是改善男子和妇女的生殖健康，从而促进生育健康和需要的儿童。这个应用程序的目标是成为合作多中心生殖医学网络（CMRMN）的一部分。我们致力于合作研究，并提供一个庞大的患者基础（包括异常高比例的少数民族），从中招募受试者进入网络协议。我们建议通过证明韦恩州立大学的研究专长和资源与成功参与网络是一致的，来实现这一目标；通过提供韦恩州立大学在合作临床研究方面的承诺和记录的证据；通过提供一个“概念”协议来证明我们有能力构思和设计一个合作项目。我们期望在其他成员确定的研究中，我们将成为CMRMN不可或缺的和有贡献的成员，并作为新项目的创新者。特别是，我们将有助于全基因组筛选遗传差异，可以解释生殖异常的发病机制。我们的长期研究目标之一是确定男性不育的先天性和获得性遗传原因，以便为考虑将辅助生殖技术作为不育解决方案的受影响夫妇提供高度针对性的咨询和/或治疗。我们的概念方案的具体目标是通过微阵列技术的创新应用，识别与男性因素不育密切相关的基因。这项研究的中心假设是，与有生育能力的男性相比，不育男性精子中含有的基因转录物（mRNA物种）在质量和数量上都有所不同，从而可以确定“不育基因”的候选基因。其基本原理是，一旦通过合作全基因组筛选确定了候选基因，就可以制定假设驱动的研究，以确定它们是否与一种或多种男性因素不育的遗传形式随意相关。我们将通过追求两个具体目标来检验我们的中心假设：1)确定可育男性精子中基因转录谱变化的程度；2)鉴定不育男性与有生育能力男性精子中表达不同的基因转录本。CMRMN对议定书的成功完成至关重要；它将确保准确解释结果所需的权力。拟议的转化研究是创新的，因为它结合了临床和基础分子遗传学专业知识的合作努力，将采用新的分析（微阵列）技术，以经济有效的方式获得男性因素不育的遗传原因的线索。结果将是重要的，因为它们将为对男性生育能力产生负面影响的遗传因素进行明确分析提供基础，从而导致对男性因素不育的遗传原因进行高度准确、廉价的诊断测试，并在某些情况下允许开出特定替代疗法的处方。

Our overall goal is to improve the reproductive health of men and women, thereby fostering the birth of healthy and wanted children. The objective of this application is to become part of the Cooperative Multicenter Reproductive Medicine Network (CMRMN). We are committed to cooperative research and offer a large patient base (including an unusually high percentage of minorities) from which to enroll subjects into Network protocols. We propose to achieve this objective by documenting that Wayne State's spectrum of research expertise and resources is consistent with successful participation in the Network; by providing evidence of Wayne State's commitment and track record in cooperative clinical research; and by providing a 'concept' protocol as proof of our ability to conceive and design a cooperative project. It is our expectation that we would be an integral and contributing member of the CMRMN in research identified by other members, and as an innovator of new projects. In particular, we would contribute to genome-wide screening for genetic differences that could explain the pathogenesis of reproductive abnormalities. One of our long-range research goals is to identify congenital and acquired genetic causes of male infertility, so that highly specific counseling and/or therapy can be offered to affected couples considering assisted reproductive technologies as a solution to infertility. The specific objective of our concept protocol is to identify genes, through the innovative application of microarray technology, closely associated with male factor infertility. The central hypothesis for the proposed research is that gene transcripts (mRNA species) contained in the sperm of infertile males will differ qualitatively and quantitatively, compared to those of fertile men, thereby allowing candidates for 'infertility genes' to be identified. The rationale is that once candidate genes have been identified by cooperative genome-wide screening, hypothesis-driven research can be formulated to determine whether they relate casually to one or more genetic forms of male factor infertility. We will test our central hypothesis by pursuing two specific aims: 1) identify the extent to which the profile of gene transcripts varies in the sperm of fertile males; and 2) identify gene transcripts that are expressed differently in the sperm of infertile, compared to fertile, men. The CMRMN is vital to successful completion of the protocol; it will assure the power needed to interpret results accurately. The proposed translational research is innovative because it combines clinical and basic molecular genetic expertise in a cooperative effort that will employ new analytical (microarray) technology to cost- effectively obtain clues to the genetic causes of male factor infertility. The outcomes will be significant because they will provide the foundations for definitive analysis of genetic factors that negatively affect male fertility, thereby leading to highly accurate, inexpensive diagnostic tests for genetic causes of male factor infertility, and in some cases, allow the prescription of specific replacement therapy.