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.

项目总结