Small Molecule Src-2 Antagonists as Regulators of Sertoli Cell Function and Male

小分子 Src-2 拮抗剂作为支持细胞功能和男性的调节剂

• 批准号: 8536443
• 负责人: DAVID M LONARD
• 金额: $ 21.91万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-24 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536443
• 关键词: Affect; Animals; Binding; Biological Models; Biology; Cell Culture Techniques; Cell physiology; Cellular biology; Chemistry; China; Contraceptive Agents; Defect; Development; Dose; Energy Metabolism; FGR gene; Fertility; Fertility Agents; Genes; Genetic; Genetic Transcription; Glycolysis; Gossypol; Image; Infertility; Instruction; Laboratories; Lead; Link; Lipids; Male Contraceptive Agents; Male Infertility; Metabolic; Metabolism; Monitor; Mus; Nuclear Receptors; Pathway interactions; Phenocopy; Proteins; Puberty; Reporter; Reproduction; Risk; Role; Screening procedure; Series; Steroid Receptors; System; Testing; Time; Transgenic Animals; Transgenic Organisms; age related; base; design; high throughput screening; hyperkalemia; improved; in vivo; male; men; mouse model; novel; nuclear receptor coactivator 1; protein function; sertoli cell; small molecule; small molecule libraries; sperm cell; tool

The Steroid Receptor Coactivators are master regulators of nuclear receptors. Specifically, SRC-2 serves as a regulator of male reproduction and is preferentially expressed in Sertoli cells. SRC-2'^' males are able to produce sperm at tlie onset of pulserty, but quickly become infertile. This loss of male fertility is due to defects in Sertoli cell function which raises the possibility that effective anti-SRC-2 small molecule antagonists (SMAs) can be developed as male contraceptive agents. Gossypol was tested as a male contraceptive agent in ~10,000 men in China and was found to be well tolerated at the doses tested and was effective as an anti-fertility agent 99% of the time. However, due to the risic of inreversible infertility and hyperkalemia, its use as a contraceptive agent was abandoned. Interestingly, gossypol treated animals develop defects in Sertoli cell biology that are strikingly similar to that seen in SRC-2''' mice. Genetic disruption of SRC-2 and gossypol treatment both result in teratozoospermia and age dependent-iike testicular degeneration. Sertoli cells of both SRC-2''' and gossypol-treated mice accumulate lipid, indicative of a common defect in Sertoli cell metabolism. In preliminary screening for SRC-2 SMIs in our laboratory, we have identified several gossypol derivatives that can disrupt the coactivator function of SRC-2. We have already completed high throughput screening campaigns for SMAs against SRC-1 and SRC-3 and are initiating a similar effort for SRC-2 as well. Because of the strong link between SRC-2, gossypol, Sertoli cell biology and male infertility, we propose to screen and characterize new SRC-2 S M ^ as a novel class of male contraceptive agents. In conjunction with support for compound chemistry that exists in this U54 application, we expect to generate SRC-2-targeting male contraceptive agents with the potential to be clinically viable.

类固醇受体共激活因子是核受体的主要调节因子。具体来说，SRC-2作为