Actions of Immunophilins in Penile Nerve Function

描述（由申请人提供）：最近发表的工作表明，亲免素配体FK 506在大鼠模型中有效保护阴茎神经支配免于变性，并在海绵体神经挤压损伤后保持阴茎勃起。这项工作与其他神经生物学研究领域的最新研究相吻合，这些研究表明亲免疫素在神经系统中含量丰富，并且它们在神经功能的多个领域中发挥重要作用，例如神经保护，神经营养影响的介导和神经递质释放。保护勃起功能的亲免素配体的确切分子机制仍然未知。阐明这些机制可能会提供额外的独特见解的功能作用的immunophilins和定义新的药理学治疗勃起功能障碍与神经源性疾病的目标。开发治疗勃起功能障碍的新策略的重要性是可以理解的，考虑到这种情况被认为会影响10%至20%的美国男性人口，并带来巨大的生活质量影响和与其他健康并发症的关联。该研究计划集中在两个主要研究领域，与immunophilins及其各自配体在阴茎神经功能方面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功能的immunophilin配体在促进海绵体神经损伤后勃起功能恢复方面的作用。具体目标是：（1）鉴定分别介导阴茎神经保护和神经再生的亲免素受体蛋白及其信号通路;（2）区分钙调神经磷酸酶依赖的神经营养作用，（免疫抑制剂）亲免素配体和钙调神经磷酸酶非依赖性（非免疫抑制剂）亲免素配体对海绵体神经损伤后勃起功能的影响;（3）评价神经型一氧化氮合酶在阴茎海绵体神经损伤后免疫亲素神经营养作用中的作用;（4）评价免疫亲素对阴茎海绵体神经损伤后神经营养素神经营养作用的影响。本文所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.