Serotonin Receptor Modulation of Neurotrophic Factors in the Retina

视网膜神经营养因子的血清素受体调节

• 批准号: 8448258
• 负责人: MARK E PENNESI
• 金额: $ 16.48万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448258
• 关键词: Adverse effects; Affect; Amacrine Cells; Animal Model; Antibodies; Anxiety; Basic Science; Blindness; Brain; Brain-Derived Neurotrophic Factor; Cell Surface Receptors; Cell physiology; Cells; Central Nervous System Part; Cessation of life; Ciliary Neurotrophic Factor; Clinic; Clinical; Clinical Sciences; Clinical Trials; Complete Blindness; Data; Degenerative Disorder; Deterioration; Development Plans; Disease; Doctor of Philosophy; Drug Implants; Electrodes; Electrophysiology (science); Environment; Enzyme-Linked Immunosorbent Assay; Eye; FDA approved; Fluoxetine; Funding; Future; Genetic; Genetic Transcription; Goals; Grant; Growth Factor; Health Sciences; Human; Immunohistochemistry; Inherited; Injection of therapeutic agent; Institutes; Institution; Knowledge; Lead; Light; Measures; Mediating; Mental Depression; Mental disorders; Mentors; Modeling; Mus; Oral; Oregon; Paroxetine; Patients; Pharmaceutical Preparations; Photoreceptors; Physiology; Principal Investigator; Program Development; Property; Public Health; Rare Diseases; Receptor Activation; Research; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Rodent; Rodent Model; Role; Scientist; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Agonists; Structure of retinal pigment epithelium; System; Techniques; Testing; Time; Tissues; Topical agent; Training Programs; Translating; Translational Activation; United States; United States National Institutes of Health; Universities; Vision; Visual; Western Blotting; career; career development; cell type; depressive symptoms; effective therapy; experience; ganglion cell; in vivo; inherited retinal degeneration; inhibitor/antagonist; interest; intravitreal injection; neurotrophic factor; novel strategies; prevent; professor; public health relevance; receptor; research study; response; serotonin receptor; serotonin transporter; translational clinical trial

DESCRIPTION (provided by applicant): This proposal describes a research plan and a 5-year mentored training program for the development of an academic career studying inherited retinal degenerations at the Casey Eye Institute at the Oregon Health & Science University (OHSU). The principal investigator, Mark Pennesi, MD/PhD, has a long-standing interest in studying retinal degeneration. As a newly appointed Assistant Professor at the Casey Eye Institute, he is pursuing a career path as a clinician scientist who sees patients with inherited retinal degenerations in the clinic, and also performs bench top research to understand these diseases and develop new therapies for them. As one of the premier NIH funded institutions, OHSU provides a unique environment for him to pursue basic science research, and also has the capacity to turn this research into clinical trials through its newly formed Translational Clinical Trials Center. The proposed career development plan will be composed of both research and clinical components. Richard Weleber, MD, Peter Francis, MD/PhD, and Rowland Taylor, PhD will all serve as mentors in different capacities. Dr. Weleber is a Professor at OHSU who will provide over thirty-five years of experience with inherited retinal degenerations as well as a vast knowledge of clinical electrophysiology. Dr. Francis is an Associate Professor at OHSU and is a clinician scientist with a strong clinical and basic science background in ophthalmic genetics. He has been involved in several translational projects including three clinical trials for retinal degenerations. Dr. Taylor is an Associate Professor at the Casey Eye Institute and has an extensive background in retinal electrophysiology and retinal immunohistochemistry. The focus of his research will be to develop new treatments for retinal degenerations such as Retinitis Pigmentosa (RP). RP is the most common causes of inherited blindness in the United States. There are currently no effective treatments to halt the visual deterioration in RP. Neurotrophic factors such as ciliary neurotrophic factor (CNTF) and brain derived neurotrophic factor (BDNF) have been shown to prevent photoreceptor death in animal models of RP13-17, but such treatments require frequent injections or implanted drug release systems. An oral or topical medication that could up-regulate protective neurotrophic factors would result in a paradigm shift in the treatment for RP. One novel approach might be to increase the levels of neuroprotective growth factors, such as BDNF in the retina by administering oral selective serotonin reuptake inhibitors (SSRIs). SSRIs, such as fluoxetine or paroxetine, have been widely and safely used to treat a number of psychiatric diseases such as depression and anxiety. There is mounting evidence showing that the anti-depressive effects of SSRIs result from increased expression of BDNF in the brain18. Since SSRIs are already FDA approved drugs, positive findings from this study could rapidly translate to human clinical trials for currently incurable retinal diseases. The hypothesis of this proposal is that administration of SSRIs or serotonin receptor modulators (SRMs) will elevate levels of BDNF in the retina by facilitating its release from retinal pigment epithelium (RPE) cells thereby preventing retinal degeneration in rodent models of RP. The first specific aim will characterize the presence and distribution of serotonin receptors, serotonin transporters in the mouse and human retina and RPE. The second specific aim of this grant will determine whether SSRIs or other SRMs might have side effects on visual function by measuring the effects of these drugs on light responses in the rodent retina using electrophysiological techniques, such as the ERG and the multi-electrode array. The final specific aim of this grant will determine if serotonin receptor agonists, antagonists or SSRIs can modulate the levels of BDNF in cultured RPE.

描述（由申请人提供）：该提案描述了一项研究计划和一项为期5年的指导培训计划，以开发研究俄勒冈州健康与科学大学（OHSU）Casey Eye Institute的遗传性视网膜退化的学术职业生涯。主要研究员Mark Pennesi，医学博士/博士学位对研究视网膜变性具有长期的兴趣。作为凯西眼科研究所（Casey Eye Institute）的新任命的助理教授，他正在作为临床科学家的职业道路，他看到诊所中有遗传性视网膜退化的患者，并且还进行了基准顶级研究以了解这些疾病并为他们开发新的疗法。作为NIH资助的主要机构之一，OHSU为他提供了一个独特的环境，可以通过其新成立的转化临床试验中心将这项研究转变为临床试验。 拟议的职业发展计划将由研究和临床组成部分组成。医学博士Richard Weleber，医学博士/博士学位和罗兰·泰勒（Rowland Taylor）博士都将担任不同能力的导师。 Weleber博士是OHSU的一位教授，他将提供三十五年的遗传性视网膜变性以及对临床电生理学的广泛了解。弗朗西斯（Francis）博士是OHSU的副教授，是一名临床医学家，在眼科遗传学方面具有强大的临床和基础科学背景。他参与了几个翻译项目，包括三项视网膜退化的临床试验。泰勒博士是Casey Eye Institute的副教授，在视网膜电生理学和视网膜免疫组织化学方面具有广泛的背景。 他的研究重点是开发新的视网膜变性治疗方法，例如色素性视网膜炎（RP）。 RP是美国遗传失明的最常见原因。目前没有有效的治疗方法可以阻止RP的视觉恶化。已经证明，神经营养因子（例如睫状神经营养因子（CNTF）和脑衍生的神经营养因子（BDNF））已证明在RP13-17的动物模型中可以防止感光因素死亡，但是此类治疗需要经常注射或植入的药物释放系统。可以上调保护性神经营养因素的口服或局部药物会导致RP治疗的范式转移。 一种新的方法可能是通过施用口服选择性5-羟色胺再摄取抑制剂（SSRIS）来增加视网膜中神经保护生长因子的水平。 SSRI，例如氟西汀或帕罗西汀，已被广泛，安全地用于治疗许多精神病，例如抑郁和焦虑。有越来越多的证据表明，SSRI的抗抑郁作用是由于Brain中BDNF表达增加而导致的。由于SSRI已经是FDA批准的药物，因此这项研究的阳性发现可能会迅速转化为目前无法治愈的视网膜疾病的人类临床试验。该提案的假设是，通过促进其从视网膜色素上皮细胞（RPE）细胞释放，从而在视网膜中释放了SSRI或5-羟色胺受体调节剂（SRMS）将升高BDNF的水平，从而防止RP啮齿动物模型中的视网膜变性。第一个具体目的将表征5-羟色胺受体，小鼠和人视网膜和RPE中5-羟色胺转运蛋白的存在和分布。该赠款的第二个具体目的将通过使用电生理技术（例如ERG和多电极阵列）来测量这些药物对啮齿动物视网膜中光反应的影响来确定SSRI或其他SRM是否可能对视觉功能产生副作用。该赠款的最终特定目的将确定5-羟色胺受体激动剂，拮抗剂或SSRI是否可以调节培养的RPE中的BDNF水平。