青春期阴茎增大的关键分子机制：雄激素—赖氨酰氧化酶—白膜重塑的调控研究

Micropenis is an unsolved problem in clinical practice. To provide the treatment ideas from a new perspective, it is urgent to clarify the key mechanisms of penis enlargement in puberty. It has been proved that there is a drastic change in androgens during puberty, and tunica albuginea remodeling is the important mechanism in penis development. Our previous studies indicate that the Lysyl Oxidase (LOX) level of the rats’ penis decreased significantly after puberty, and the adult rats’ penis is prolonged significantly after anti-LOX treatment but the erectile function is not affected. So, we hypothesize: LOX and androgen lead to remodeling of the tunica albuginea and further promote penis enlargement, which may be regulated via TGF-β pathway in rat's penis development. To verify this hypothesis, the following specific aims are proposed: (1) determine the LOX and androgen levels in rats of different ages; (2) explore the effect of androgen and LOX on tunica albuginea remodeling; (3) delineate the cascade of TGF-β pathway in penis development using gene knockout mice. The answers to the above aims will provide us with novel insight of penis development, which may provide new treatment ideas for patients with micropenis.

阴茎短小是临床上无法解决的难题，亟需阐明阴茎增大的关键机制，以便从全新的角度提供治疗措施。已有研究证实：男性雄激素的水平在青春期前后剧烈变化；白膜重塑系阴茎快速发育的重要机制。我们前期研究表明：青春期后，大鼠阴茎赖氨酰氧化酶(Lysyl Oxidase, LOX)的水平显著下降；青春期及成年大鼠进行抗LOX治疗后，阴茎均显著延长，且勃起功能不受影响。由此我们提出假设：在大鼠的阴茎发育过程中，雄激素与LOX共同导致白膜重塑促进阴茎增大，其机制与TGF-β信号通路相关。为验证此假设，本项目围绕“不同周龄大鼠雄激素及LOX水平变化”，“雄激素与LOX对阴茎白膜重塑的影响”，“利用基因敲除小鼠研究雄激素—TGF-β信号通路—LOX在白膜重塑中的机制”等问题开展一系列的基础研究。力争阐明青春期阴茎增大的关键机制，为阴茎短小的患者提供新的治疗思路。

阴茎短小男性遭受着严重的性功能障碍与心理问题。然而，阴茎短小是目前临床上无法解决的难题，阴茎短小的干预仍面对着巨大的挑战。先前研究提示，雄激素与赖氨酰氧化酶（Lysyl Oxidase, LOX）可能共同参与阴茎白膜重塑从而影响青春期大鼠的阴茎发育。为了探索是否干预雄激素、LOX 和（或）联合负压助勃器能够有效实现延长阴茎组织的目的。首先，年龄组大鼠进行去势处理以了解雄激素与LOX是否存在交互关系；其次，青春期与成年期大鼠均施以抗LOX和（或）负压助勃装器干预，以探索其是否实现延长阴茎组织的目的。经干预后发现，去势使阴茎组织LOX表达进一步下降；青春期和成年期大鼠阴茎长度在抗LOX和（或）负压助勃干预后均显著延长，且各组大鼠勃起功能无明显差异；进一步发现，抗LOX通过抑制LOX活性、减少胶原蛋白的成熟交联，引起阴茎白膜重塑，在此基础上施加负压助勃器的机械应力，阴茎白膜重塑更加明显、阴茎延长效果也更为显著。这些结果将对未来干预临床阴茎短小提供理想的靶标。