The Neuroprotective Effect of HSP72 Induction in Experimental Glaucoma

HSP72 诱导对实验性青光眼的神经保护作用

• 批准号: 8323418
• 负责人: NATIK PIRI
• 金额: $ 25.61万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323418
• 关键词: Affect; Affinity; Animals; Apoptosis; Apoptotic; Axon; Binding; Blindness; Blood flow; Cell Death; Cell Survival; Cells; Characteristics; Chickens; Chronic; Complement; Cytomegalovirus; Cytoprotection; Disease; Disease Progression; Early Promoters; Electroporation; Enhancers; Evaluation; Fever; Ganglion Cell Layer; Genes; Glaucoma; Glutamates; HSP72 protein; Heat-Shock Proteins 70; Homeostasis; Hybrids; Immunoblotting; Immunohistochemistry; Immunologics; Immunoprecipitation; Label; Long-Term Effects; Mediating; Messenger RNA; Modeling; Molecular; N-terminal; Neurons; Neuropathy; Neuroprotective Agents; Nitric Oxide; North Carolina; Optic Nerve; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phosphotransferases; Physiologic Intraocular Pressure; Plasmids; Process; Production; Protein Array; Proteins; Rattus; Reporting; Research; Retina; Retinal; Retinal Ganglion Cells; Risk Factors; Role; Screening procedure; Serotyping; Small Interfering RNA; Stimulus; Stress; Techniques; Therapeutic; Therapeutic Agents; Transfection; Universities; Vaccination; Viral; Visual Fields; Yeasts; Zinc; arimoclomol; base; beta Actin; cell type; design; excitotoxicity; experience; expression vector; gene therapy; geranylgeranylacetone; improved; in vivo; intravitreal injection; neuronal cell body; neuroprotection; neurotrophic factor; overexpression; promoter; protective effect; protein expression; protein protein interaction; stress-activated protein kinase 1; therapeutic target; vector; yeast two hybrid system

ABSTRACT The long-term objective of our research is to develop a neuroprotective strategy that will complement the current treatment of glaucoma with IOP reduction. Our hypothesis is that long-term pharmacological induction of Hsp72 (the inducible form of heat shock protein 70) expression can protect RGCs from glaucomatous damage. This hypothesis is based on the wide range of cytoprotective capacities of HSP72, which may be explained by its ability to inhibit several apoptotic pathways. Specific aims of the proposal are: Aim 1. Determine the effect of Hsp72 overexpression on RGC survival in a rat glaucoma model. Adeno- associated viral (AAV, serotype 5) based vectors carrying the HSP72 gene (AAV-HSP72) will be used to deliver and express the corresponding protein in RGCs, which is the primary target for neuroprotection. Specific overexpression of HSP72 in glaucomatous retinas will allow us to evaluate its neuroprotective effect. Aim 2. Elucidate the mechanisms of inhibition of apoptotic pathways by HSP72 in experimental glaucoma. HSP72 is known to inhibit multiple pathways leading to cell death and its anti-apoptotic functions are associated with binding to apoptosis protease activating factor-1 (Apaf-1), apotosis-inducing factor (AIF) and c-Jun N-terminal kinase (JNK). The involvement of these and other potential mechanisms of RGC protection by HSP72 in experimental glaucoma will be studied. The results of these studies will help us define HSP72 neuroprotective mechanisms and better understand RGC apoptosis in glaucoma. Aim 3. Evaluate the therapeutic potential of pharmacological induction of HSP72 for glaucoma. We will study GGA and arimoclomol, HSP72 co-inducers, as potential therapeutic agents for protection of RGCs in the rat glaucoma model. The role of HSP72 in GGA and arimoclomol mediated neuroprotection will be analyzed by inhibition of HSP72 expression with small interfering RNA (siRNA) designed to degrade HSP72 mRNA. The proposal is intended to comprehensively evaluate the Hsp72 neuroprotective effect in experimental glaucoma and understand the mechanisms of its action on apoptotic pathways. We believe that the cytoprotective and anti-apoptotic characteristics of HSP72 and the possibility to pharmacologically induce expression of this protein in cells experiencing stress make this protein an attractive therapeutic target for glaucoma neuroprotection. The ability of HSP72 to protect cells from a variety of stress stimuli is an important factor in designing a strategy to preserve RGCs in glaucoma, since the cellular damage in this disease may be caused by different molecular mechanisms that have a common final pathway of characteristic optic nerve damage and visual loss.

摘要