Actions of Immunophilins in Penile Nerve Function

描述（由申请人提供）：最近发表的研究表明，在大鼠模型中，亲免疫蛋白配体FK506有效地保护阴茎神经支配免受变性，并保持海绵体神经挤压损伤后的阴茎勃起。这项工作与最近在其他神经生物学研究领域的研究相吻合，这些研究表明，亲免疫蛋白在神经系统中含量丰富，它们在神经功能的多个领域发挥重要作用，如神经保护、神经营养影响的调解和神经递质释放。亲免疫蛋白配体维持勃起功能的确切分子机制尚不清楚。阐明这些机制可能会对亲免疫蛋白的功能作用提供额外的独特见解，并为治疗与神经源性疾病相关的勃起功能障碍确定新的药理学靶点。考虑到美国10%到20%的男性受到勃起功能障碍的影响，并对生活质量产生巨大影响，并与其他健康合并症有关，开发治疗勃起功能障碍新策略的重要性是可以理解的。本研究主要集中在两个研究领域，即亲免疫蛋白及其配体对阴茎神经功能的功能性神经营养作用的相关分子机制，以及具有非免疫抑制特性的亲免疫蛋白配体在促进海绵神经损伤后勃起功能恢复中的作用。具体目的是：(1)研究在阴茎中分别介导神经保护和神经再生的亲免疫蛋白受体蛋白及其信号通路；(2)区分钙调磷酸酶依赖性（免疫抑制性）亲免疫蛋白配体和钙调磷酸酶非依赖性（非免疫抑制性）亲免疫蛋白配体对海绵穴神经损伤后勃起功能的神经营养作用；(3)探讨神经元型一氧化氮合酶在海绵状神经损伤后阴茎内亲免疫蛋白的神经营养作用中的作用；(4)评价亲免疫蛋白对海绵状神经损伤后阴茎神经营养蛋白作用的影响。本文描述的实验工作结合了分子生物学、勃起生理学和形态学研究。

DESCRIPTION (provided by applicant): Recently published work has shown that the immunophilin ligand FK506 potently protects penile innervation from degeneration and preserves penile erection after cavernous nerve crush injury in a rat model. This work has coincided with recent investigations in other neurobiologic research fields which have shown immunophilins are abundantly contained in the nervous system and they assume important roles in multiple areas of neural function, such as neuroprotection, mediation of neurotrophic influences, and neurotransmitter release. The exact molecular mechanisms exerted by immunophilin ligands that preserve erectile function remain unknown. Elucidation of such mechanisms may afford additional unique insights into the functional roles of immunophilins and define new pharmacologic targets for treating erectile dysfunction associated with neurogenic disorders. The importance of developing new strategies for treating erectile dysfunction is understandable when considering that the condition is recognized to affect 10 to 20% of the American male population and carry enormous quality of life ramifications and associations with other health co-morbidities. The research proposal centers on two primary research areas, the molecular mechanisms associated with the functional neurotrophic effects of immunophilins and their respective ligands in reference to penile nerve function, and the action of immunophilin ligands with non-immunosuppressant features in promoting erectile function recovery after cavernous nerve injury. Specific aims are: (1) to characterize the immunophilin receptor proteins and their signaling pathways respectively mediating neuroprotection and neuroregeneration in the penis; (2) to distinguish the neurotrophic effects of calcineurin-dependent (immunosuppressant) immunophilin ligands and calcineurin-independent (non-immunosuppressant) immunophilin ligands on erectile function after cavernous nerve injury; (3) to evaluate the role of neuronal nitric oxide synthase in the neurotrophic actions of immunophilins in the penis after cavernous nerve injury; and (4) to evaluate the influence of immunophilins on the neurotrophic actions of neurotrophins in the penis after cavernous nerve injury. The experimental work described herein combines molecular biologic, erection physiologic, and morphologic studies.