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Investigating Membrane Trafficking Deficits in Choroideremia

研究无脉络膜血症的膜运输缺陷

基本信息

批准号：
10469438
负责人：
Abigail Fahim
金额：
$ 23.76万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469438
关键词：
Address Age related macular degeneration Atrophic Award Biological Assay Blindness Blood Vessels CRISPR/Cas technology Cell Culture Techniques Cell Line Cell Proliferation Cell Survival Cells Cessation of life Childhood Choroid Choroideremia Communication Comparative Study Defect Degenerative Disorder Derivation procedure Development Disease Drug Targeting Endothelial Cells Equilibrium Eye diseases Functional disorder Future Genes Goals Growth Factor Histopathology In Vitro Inherited Investigation Knowledge Laboratories Lead Leadership MT3 gene Maintenance Mass Spectrum Analysis Mediating Membrane Membrane Lipids Mentors Mentorship Modeling Mutation Pathologic Pathway interactions Patients Phenotype Photoreceptors Professional Competence Protein Secretion Proteins Rab escort protein Reporting Research Personnel Resources Retina Retinal Degeneration Retinal Diseases Role Signaling Molecule Site Small Interfering RNA Structure of retinal pigment epithelium Technical Expertise Techniques Testing Therapeutic Training Vascular blood supply Wallerian Degeneration Work career career development cell type cytokine drug development experimental study growth inhibitory proteins high throughput screening human stem cells induced pluripotent stem cell knock-down monolayer mouse model novel novel therapeutic intervention overexpression photoreceptor degeneration prenylation programs protein transport rab GTP-Binding Proteins screening skills small molecule stem cell biology stem cells targeted treatment therapeutic target trafficking vascular bed young adult

项目摘要

SUMMARY: Death of the choroid, the vascular bed underlying the retina, is a prominent pathologic hallmark of numerous inherited retinal degenerative diseases as well as age-related macular degeneration (AMD). Choroidal death is likely impacted by dysfunction of the retinal pigment epithelium (RPE), a monolayer of cells between the photoreceptors and the choroid. A critical knowledge gap impeding progress in therapeutic strategies is how RPE dysfunction contributes to choroidal death. Choroideremia is an inherited chorioretinal degeneration leading to early blindness with no current treatment. Several lines of evidence implicate the RPE as the primary site of degeneration, with secondary degeneration of the photoreceptors and choroid. The causative genetic defect is deficiency of CHM, encoding Rab escort protein 1 (REP-1), which facilitates prenylation of Rab GTPases, a critical step in membrane trafficking. RPE cells are highly polarized and differentially secrete numerous growth factors and signaling molecules in a directional manner towards the photoreceptors and choroid. The proposed studies will elucidate how RPE membrane trafficking defects in choroideremia alter protein secretion and how this impacts choroidal survival. The long-term goal of this work is to develop the necessary skills and expertise to establish an independent career focused on therapies targeting RPE dysfunction in retinal degenerative disease. The scientific objective is to understand mechanisms of choroidal death. We will test the hypothesis that alterations in RPE secretion of proteins in the vascular survival pathway lead to choroidal atrophy in choroideremia using a human stem cell derived RPE model. The career development objectives are to master stem cell culture and RPE derivation techniques, to develop expertise in membrane trafficking pathways of RPE, to become proficient in the techniques and principles of therapeutic target discovery, and to develop skills in leadership, mentorship, and scientific communication necessary to become a successful independent investigator. The proposed study will increase the candidate’s understanding of choroideremia and identify therapeutic targets in this untreatable blinding disease, which may also have broader implications for choroidal degeneration in AMD and other chorioretinal degenerative diseases.

脉络膜（视网膜下的血管床）的死亡是视网膜病变的一个重要病理标志