Biology of the Blood-Testis Barrier

血睾屏障的生物学

基本信息

批准号：
8613215
负责人：
C. Yan Cheng
金额：
$ 39.41万
依托单位：
POPULATION COUNCIL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8613215
关键词：
Actin-Binding Protein Actins Acute Address Adherens Junction Adhesives Apical Basement membrane Biological Biology Blood Blood-Testis Barrier Bundling Cadmium Cell Adhesion Cell membrane Collagen Complex Contraceptive Agents Developed Countries Developing Countries Development Diethylstilbestrol Dose Endoplasmic Reticulum Endosomes Epidermal Growth Factor Receptor Pathway Substrate 8 Epithelial Epithelium Event F-Actin Fertility Functional disorder Gelatinase A Gelatinase B Generations Genes Genetic Models Grant Homeostasis In Vitro Intercellular Junctions Journals Knock-out Laboratories Laminin Lead Lifting Light Male Contraceptive Agents Male Infertility Mammals Mediating Meiosis Metalloproteases MicroRNAs Microfilaments Molecular Mus Nature Neonatal Neurons Peer Review Peptides Production Proteins Publications RNA Interference Rattus Regulation Research Research Personnel Rodent Role Seminiferous tubule structure Small Interfering RNA Small RNA Spermatids Spermatocytes Spermatogenesis Staging Steroids Structure Techniques Testis Testosterone Tissues Toxic Environmental Substances Training Wiskott-Aldrich Syndrome autocrine bisphenol A cytokine design genetic regulatory protein in vivo insight male men novel novel therapeutic intervention overexpression phthalates piRNA polymerization protein transport public health relevance reproductive research study sertoli cell small molecule spatiotemporal sperm cell spermatogenic epithelium structure therapeutic development toxicant xenoestrogen

项目摘要

Project Summary/Abstract. In the mammalian testis, spermatogenesis takes place in the epithelium of the seminiferous tubule, the functional unit that produces millions of spermatozoa daily. The blood-testis barrier (BTB), located near the basement membrane (BM) of the seminiferous epithelium, confers gate-keeper and the fence function, which restricts the paracellular and transcellular transport of harmful substances such as toxicants across the barrier, respectively, to maintain spermatogenesis. The BTB also physically divides the seminiferous epithelium into a basal and an adluminal compartment; thus, meiosis I and II, and post-meiotic spermatid development take place in a specialized microenvironment (i.e., the adluminal compartment) behind the BTB. The BTB is one of the tightest blood-tissue barriers in mammals since cell junctions at the BTB are reinforced by bundles of actin filaments that lie perpendicular to apposing Sertoli cell plasma membranes, which are only found in the testis. However, the BTB is a dynamic structure, undergoing extensive restructuring at stage VIII of the epithelial cycle so that preleptotene spermatocytes can cross the BTB and enter the adluminal compartment for further development. It is now well established that a functional BTB is crucial for spermatogenesis. Studies completed in the past grant period have shown that BTB function is regulated by biologically active peptides released (i) at the apical ectoplasmic specialization (apical ES, a testis-specific adherens junction at the Sertoli-spermatid interface), and (ii) at the basement membrane (BM) mediated by a functional axis designated the apical ES-BTB-BM axis. In short, biologically active fragments of laminin and collagen chains released at the apical ES and the BM, respectively, act as autocrine factors to regulate BTB function in this axis. Herein, we will continue this important research to understand the underlying molecular mechanism(s) that regulates BTB function. First, we will unravel the mechanism(s) by which these fragments regulate Sertoli cell adhesion and BTB restructuring via their effects on the F-actin network at the BTB, such as actin binding and regulatory proteins. We will also examine the involvement of endosome-mediated protein trafficking and small regulatory RNAs in these events using state-of-the-art techniques and approaches. Second, we will identify the biological significance of biomolecules, such as cytokines, steroids and matrix metalloproteases, in regulating the stage-specific production of these bioactive peptides during the epithelial cycle of spermatogenesis. These findings will have a significant impact in understanding the biology of BTB in spermatogenesis. More important, these findings will shed new light on the development of novel reversible non-hormonal contraceptives for men. For instance, peptides derived from the apical ES and BM can be developed into contraceptives to perturb BTB function and impair spermatogenesis. Additionally, these findings can lead to the development of new therapeutic approaches to interfere with toxicant-induced male reproductive dysfunction, which is one of the leading causes of the decline in male fertility. For instance, the environmental toxicant cadmium mediates its effects at the BTB to induce male reproductive dysfunction; these findings provide crucial information in the design and synthesis of small molecules that either reverse or block cadmium-induced BTB disruption that leads to male infertility.

项目摘要/摘要。在哺乳动物睾丸中，精子发生发生在睾丸上皮细胞中生精小管，每天产生数百万精子的功能单位。血睾屏障（BTB）位于生精上皮的基底膜（BM）附近，赋予看门人和栅栏功能，限制有害物质的细胞旁和跨细胞运输，例如分别穿过毒物屏障，维持精子发生。 BTB 还在物理上划分了生精上皮分为基底室和腔室；因此，减数分裂 I 和 II 以及减数分裂后精子细胞的发育发生在特殊的微环境（即腔内室）中落后于BTB。 BTB 是哺乳动物中最紧密的血液组织屏障之一，因为 BTB 由垂直于并列支持细胞血浆的肌动蛋白丝束增强膜，仅存在于睾丸中。然而，BTB 是一个动态结构，不断变化在上皮周期的第八阶段进行广泛的重组，以便前细线精母细胞可以穿过 BTB 并进入腔室进一步发育。现在已经确定的是功能性 BTB 对于精子发生至关重要。在过去的资助期内完成的研究表明 BTB 功能受到顶端外质特化释放的生物活性肽的调节 (i) （顶端 ES，支持精子细胞界面处的睾丸特异性粘附连接），以及 (ii) 基底膜（BM）由称为顶端 ES-BTB-BM 轴的功能轴介导。简而言之，从生物学角度来说层粘连蛋白和胶原链的活性片段分别在顶端 ES 和 BM 释放，充当自分泌因子调节该轴的 BTB 功能。在此，我们将继续这项重要的研究了解调节 BTB 功能的潜在分子机制。首先，我们将解开这些片段通过其作用调节支持细胞粘附和 BTB 重组的机制 BTB 上的 F-肌动蛋白网络，例如肌动蛋白结合蛋白和调节蛋白。我们还将检查内体介导的蛋白质运输和小调节 RNA 在这些事件中的参与最先进的技术和方法。其次，我们要明确其生物学意义。生物分子，如细胞因子、类固醇和基质金属蛋白酶，在调节特定阶段这些生物活性肽在精子发生的上皮周期中产生。这些发现将对于了解 BTB 在精子发生中的生物学具有重大影响。更重要的是，这些研究结果将为新型可逆男性非激素避孕药的开发提供新的线索。例如，源自顶端ES和BM的肽可以开发成避孕药来扰乱 BTB 功能并损害精子发生。此外，这些发现可能会导致新的开发干扰毒物引起的男性生殖功能障碍的治疗方法，这是治疗方法之一男性生育能力下降的主要原因。例如，环境毒物镉介导其 BTB 的影响会导致男性生殖功能障碍；这些发现提供了重要信息设计和合成小分子，逆转或阻止镉诱导的 BTB 破坏导致男性不育。