Actions of Immunophilins in Penile Nerve Function

描述(申请人提供)：最近发表的研究表明，免疫亲和素配体FK506有效地保护阴茎神经免于变性，并在海绵体神经挤压损伤后保存阴茎勃起。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，免疫亲和素丰富地存在于神经系统中，在神经功能的多个领域发挥着重要作用，如神经保护、神经营养影响的中介和神经递质的释放。免疫亲和素配体保护勃起功能的确切分子机制尚不清楚。这些机制的阐明可能会为免疫亲和素的功能作用提供更多独特的见解，并为治疗与神经源性疾病相关的勃起功能障碍定义新的药理靶点。考虑到勃起功能障碍被认为影响到美国10%至20%的男性人口，并具有巨大的生活质量分支和与其他健康并发症的关联，开发治疗勃起功能障碍的新策略的重要性是可以理解的。研究建议集中在两个主要研究领域，即与免疫亲和素及其各自的配体在阴茎神经功能中的功能性神经营养作用相关的分子机制，以及具有非免疫抑制特性的免疫亲和素配体在促进海绵体神经损伤后勃起功能恢复中的作用。其具体目的是：(1)鉴定分别介导海绵体神经保护和神经再生的免疫亲和素受体蛋白及其信号通路；(2)区分依赖钙调神经磷酸酶(免疫抑制剂)的免疫亲和素配体和不依赖钙调神经磷酸酶(非免疫抑制剂)的免疫亲和素配体对阴茎海绵体神经损伤后勃起功能的神经营养作用；(3)评价神经元型一氧化氮合酶在海绵体神经损伤后免疫亲和素神经营养作用中的作用；(4)评价免疫亲和素对海绵体神经损伤后阴茎神经营养素神经营养作用的影响。这里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.