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: 8029420
• 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/8029420
• 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; neurotrophic factor; novel strategies; prevent; professor; 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. PUBLIC HEALTH RELEVANCE: The goal of this project is to explore the potential of selective serotonin inhibitors and SRM to protect the retina in patients with retinal degenerative diseases that lead to blindness. While some of these diseases are rare, they can lead to complete blindness, thus making their impact on public health significant.

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，旨在发展俄勒冈健康与科学大学 (OHSU) 凯西眼科研究所研究遗传性视网膜变性的学术生涯。首席研究员 Mark Pennesi 博士/医学博士长期以来对研究视网膜变性有着浓厚的兴趣。作为凯西眼科研究所新任命的助理教授，他正在追求作为一名临床科学家的职业道路，在诊所治疗患有遗传性视网膜变性的患者，并进行基础研究以了解这些疾病并为其开发新疗法。作为 NIH 资助的首要机构之一，OHSU 为他从事基础科学研究提供了独特的环境，并且有能力通过其新成立的转化临床试验中心将这项研究转化为临床试验。 拟议的职业发展计划将由研究和临床部分组成。 Richard Weleber 医学博士、Peter Francis 医学博士/博士和 Rowland Taylor 博士都将以不同身份担任导师。 Weleber 博士是 OHSU 的教授，他将在遗传性视网膜变性方面拥有超过 35 年的经验以及丰富的临床电生理学知识。 Francis 博士是 OHSU 的副教授，也是一位临床科学家，在眼科遗传学方面拥有深厚的临床和基础科学背景。他参与了多个转化项目，包括三项视网膜变性的临床试验。泰勒博士是凯西眼科研究所的副教授，在视网膜电生理学和视网膜免疫组织化学方面拥有广泛的背景。 他的研究重点是开发治疗视网膜变性的新疗法，例如色素性视网膜炎（RP）。 RP 是美国遗传性失明的最常见原因。目前没有有效的治疗方法可以阻止 RP 视力恶化。神经营养因子如睫状神经营养因子（CNTF）和脑源性神经营养因子（BDNF）已被证明可以预防RP13-17动物模型中的光感受器死亡，但此类治疗需要频繁注射或植入药物释放系统。可以上调保护性神经营养因子的口服或外用药物将导致 RP 治疗的范式转变。 一种新方法可能是通过口服选择性血清素再摄取抑制剂 (SSRI) 来提高神经保护性生长因子的水平，例如视网膜中的 BDNF。 SSRIs，例如氟西汀或帕罗西汀，已被广泛且安全地用于治疗许多精神疾病，例如抑郁症和焦虑症。越来越多的证据表明，SSRIs 的抗抑郁作用是由于大脑中 BDNF 表达增加所致18。由于 SSRIs 已经是 FDA 批准的药物，这项研究的积极结果可以迅速转化为目前无法治愈的视网膜疾病的人体临床试验。该提议的假设是，使用 SSRI 或血清素受体调节剂 (SRM) 将促进视网膜色素上皮 (RPE) 细胞释放 BDNF，从而提高视网膜中 BDNF 的水平，从而预防 RP 啮齿动物模型中的视网膜变性。第一个具体目标将表征小鼠和人类视网膜和 RPE 中血清素受体、血清素转运蛋白的存在和分布。该资助的第二个具体目标是通过使用电生理学技术（例如 ERG 和多电极阵列）测量这些药物对啮齿动物视网膜光反应的影响，确定 SSRI 或其他 SRM 是否可能对视觉功能产生副作用。该资助的最终具体目标将确定血清素受体激动剂、拮抗剂或 SSRI 是否可以调节培养的 RPE 中的 BDNF 水平。 公共健康相关性：该项目的目标是探索选择性血清素抑制剂和 SRM 保护患有导致失明的视网膜退行性疾病患者视网膜的潜力。虽然其中一些疾病很罕见，但它们可能导致完全失明，从而对公共健康产生重大影响。