Protective Effects of Humanin on AMD Mitochondria

护脑素对 AMD 线粒体的保护作用

• 批准号: 10165719
• 负责人: MARIA C KENNEY
• 金额: $ 37.72万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165719
• 关键词: Acetylation; Age; Age related macular degeneration; Amino Acids; Animal Model; Antioxidants; Apoptosis; Apoptotic; Atrophic; Autophagocytosis; Bioenergetics; Biological; Biological Assay; Blindness; Blood Platelets; California; Cell Aging; Cell Death; Cell Nucleus; Cell Survival; Cells; Cessation of life; Clinical; Complement; Cytoprotection; Developed Countries; Disease; Elderly; Electroretinography; Enzyme-Linked Immunosorbent Assay; FPR2 gene; Genes; Genetic Transcription; Genus Hippocampus; Goals; Histology; Human; IL6ST gene; In Vitro; Individual; Inflammation; JAK2 gene; MAP2K1 gene; MAPK3 gene; Measures; Mediating; Medical; Membrane Potentials; Metabolic Diseases; Methylation; Microspheres; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Molecular Biology; Morphology; Nonexudative age-related macular degeneration; Nuclear; Oxidative Stress; Pathology; Pathway interactions; Patients; Pattern; Peptides; Pharmacotherapy; Phosphotransferases; Photoreceptors; Plasma; Production; Property; Proteins; RNA; Rattus; Reactive Oxygen Species; Retina; Retinal Degeneration; STAT3 gene; Saline; Scientist; Serum; Severities; Signal Pathway; Signal Transduction; Small Interfering RNA; Structure of retinal pigment epithelium; Supporting Cell; Surgeon; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Trypan Blue; Universities; Variant; Vision; Western Blotting; age related; analog; college; dosage; drug testing; endoplasmic reticulum stress; experimental study; extracellular; humanin; improved; in vivo; inhibitor/antagonist; knock-down; mitochondrial membrane; multidisciplinary; neovascular; novel therapeutics; precursor cell; protective effect; receptor; receptor binding

PROJECT SUMMARY Age-related macular degeneration (AMD) is one of the leading causes of vision loss in developed countries. Although several drug treatments are in use for the wet form, there is no proven medical treatment for dry AMD. AMD is associated with disruption of the mitochondrial morphology, function and mitochondrial (mt) DNA integrity. Specific mtDNA variants are associated with AMD severity. Studies of retrograde signaling between mitochondria and nuclei show that mtDNA can mediate transcription of nuclear genes related to complement, inflammation, apoptosis, cell signaling, and methylation/acetylation patterns. Mitochondrial Derived Peptides (MDPs) are recently identified biologically active, short peptides (20-27 AAs) that protect cells in vitro and in vivo. Humanin (HN), a 24 amino acid peptide, is the first MDP described and has been shown to have anti- apoptotic, neuro-protective properties supporting cell survival. HN levels decline with age and low levels have been associated with many age-related and metabolic diseases. HN represents a new class of biologically active molecules with tremendous potential to protect retinal cells from aging and oxidative stress associated with retinal pathology, such as AMD. A potent analog of HN, known as Humanin-G (HNG), will be used in this proposal since it is 1000-fold more potent than HN, giving HNG increased efficiency and cyto-protection for cells. Our Specific Aims are to test the following hypotheses: Aim 1: Cybrids with AMD mitochondria have lower levels of HN production and/or defective HN binding receptors and intracellular signaling pathways that contribute to higher levels of cell death; Aim 2: HNG-microspheres are an efficient way to deliver HNG over a long time frame in vitro and in vivo; Aim 3: Cybrids with mitochondria from Royal College of Surgeons (RCS) rats with retinal degeneration have higher levels of apoptosis, oxidative stress and cell death. Treatment with HNG will be cyto-protective to the RCS-cybrids; and Aim 4: HNG can be cyto-protective against retinal degeneration in the well-characterized RCS rat model. To test these hypotheses, we have assembled a network of three multidisciplinary clinical and basic scientists who have expertise in mitochondrial molecular biology (Dr. Cristina Kenney, University of California Irvine), Humanin and other MDPs (Dr. Pinchas Cohen, University of Southern California), and retinal degeneration animal models (Dr. Magdalene Seiler, University of California Irvine). Results from this mechanistic and translational project, will provide critical information related to whether Humanin-G may be used as a therapeutic agent to protect degenerating human retinal cells.

项目摘要 黄斑变性（AMD）是发达国家视力丧失的主要原因之一。 虽然有几种药物治疗是在使用的湿形式，有没有被证明的医学治疗干 AMD. AMD与线粒体形态、功能和线粒体（mt）DNA的破坏有关 完整特定的mtDNA变异与AMD严重程度相关。逆行信号传导的研究 线粒体和细胞核的研究表明，线粒体DNA可以介导与补体相关的核基因的转录， 炎症、凋亡、细胞信号传导和甲基化/乙酰化模式。线粒体衍生肽 MDP（MDP）是最近鉴定的具有生物活性的短肽（20-27个AA），其在体外和体内保护细胞。 vivo. Humanin（HN），一种24个氨基酸的肽，是第一个被描述的MDP，并且已经显示出具有抗肿瘤活性。 支持细胞存活的凋亡、神经保护特性。HN水平随着年龄的增长而下降， 与许多年龄相关的代谢性疾病有关。HN代表了一类新的生物学 具有巨大潜力的活性分子，可保护视网膜细胞免受衰老和氧化应激相关的损伤。 视网膜病变，如AMD。HN的有效类似物，称为Humanin-G（HNG），将用于本发明。 因为它比HN更有效1000倍，使HNG提高效率和细胞保护， 细胞我们的具体目的是测试以下假设：目的1：具有AMD线粒体的胞质杂交体具有 较低水平的HN产生和/或缺陷的HN结合受体和细胞内信号传导途径， 有助于更高水平的细胞死亡;目的2：HNG-微球是一种有效的方式来提供HNG超过 体外和体内的长时间框架;目标3：来自皇家外科医学院（RCS）的具有线粒体的胞质杂交体 患有视网膜变性的大鼠具有更高水平的细胞凋亡、氧化应激和细胞死亡。治疗 HNG对RCS-胞质杂交体具有细胞保护作用;目的4：HNG对视网膜色素变性具有细胞保护作用。 在良好表征的RCS大鼠模型中的变性。为了验证这些假设，我们收集了一个 三个多学科临床和基础科学家的网络，他们在线粒体分子生物学方面具有专业知识 生物学（Cristina肯尼博士，加州Irvine大学），Humanin和其它MDP（PinchasCohen博士， University of Southern加州）和视网膜变性动物模型（Dr. Magdalene Seiler，University of Southern California）。 加州欧文）。从这个机制和翻译项目的结果，将提供关键信息相关 Humanin-G是否可用作治疗剂以保护退化的人视网膜细胞。