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Genetic Modulators of Glaucoma

青光眼的遗传调节剂

基本信息

批准号：
10361394
负责人：
MONICA M JABLONSKI
金额：
$ 37.18万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10361394
关键词：
Age Axon Blindness Candidate Disease Gene Cell Death Cellular Assay Cessation of life Chromosome 12 Clinical Computing Methodologies Data Databases Disease Family Future Generations Genes Genetic Genetic Heterogeneity Genomics Glaucoma Goals Health Human Human Genome Inbred Strains Rats Inbreeding Investigation Laboratories Lead Methods Modeling Molecular Mus Ocular Hypertension Optic Nerve Outcome Outcome Study Pathway interactions Patients Phenotype Physiologic Intraocular Pressure Population Positioning Attribute Process Publications Quantitative Trait Loci Rattus Recombinants Regulation Research Research Personnel Retina Retinal Ganglion Cells Risk Risk Factors Rodent System Testing Therapeutic United States National Institutes of Health Validation Visual Fields Work age related cell injury cellular targeting clinical subtypes cohort deep neural network density endophenotype experience gene product genetic analysis genome wide association study human data human model lead candidate nerve damage novel novel therapeutics preservation success targeted treatment therapeutic development treatment strategy

项目摘要

Glaucoma is the leading cause of irreversible blindness in the world. While elevated intraocular pressure (IOP) is a major risk factor, damage and death of retinal ganglion cells (RGCs) underlies visual field loss. However, a thorough understanding of this disease is a major challenge because its genetic basis is heterogeneous and it represents a family of age-related disorders resulting from intersecting gene-regulated pathophysiologic networks. We propose to continue to use the BXD (C57BL/6 x DBA/2J) family of recombinant inbred (RI) lines of mice as a genetic reference panel (GRP) and to combine our work with human genome wide association studies (GWAS), to uncover and clarify the genetic heterogeneity that underlies optic nerve (ON) damage. We have had recent success using this combined approach in the regulation of intraocular pressure (IOP). We are very well positioned to take the next step and apply this approach to define cellular targets of RGC damage and death. We propose to uncover phenotypic diversities of glaucoma-related ON damage and uncover common underlying mechanisms that are shared with IOP modulation. Our long-term research goal is to identify disease mechanisms and develop neuroprotective therapies to preserve retinal health in patients at risk for glaucoma. Our overall objective is to identify novel gene products and related mechanisms that lead to glaucomatous endophenotypes using multi-dimensional genetic analyses, cross-species comparisons (mouse, rat and human) and validation using novel murine glaucoma models. Our central hypothesis is that molecular processes leading to glaucoma associated-endophenotypes, such as elevated IOP and ON damage, are shared across species, and that species comparisons can uncover common underlying mechanisms, and efficient testing of targeted glaucoma therapeutics. In the current investigation, we perform a systematic analysis of ON damage, and an additional species—rat. We will mine the extensive databases of IOP and ON damage that we are generating for more than 70 BXD strains across five age cohorts with the goal of defining new models of glaucoma. An overall strength of this proposal is the combination of cutting-edge systems genetics methods, species comparisons of glaucoma phenotypes, and a strong interdisciplinary team that includes investigators with extensive experience in systems genetics, glaucoma, GWAS in human and rats, and advanced computational methods. To test our hypothesis, we will perform the following thress studies: 1) Identify the candidate gene on chromosome 12 that modulates ON damage; 2) Determine if modulation of IOP and/or ON damage is shared across rodent species; and 3) Identify novel spontaneous glaucoma models through a comprehensive analysis of our enlarged BXD GRP of 100 or more BXD strains. The outcomes of these studies will define novel genes and molecular networks that underlie glaucoma-associated phenotypes and also provide unique glaucoma models for future analysis. These results are expected to fundamentally advance the field of glaucoma disease mechanisms and enable targeted therapeutic development.

青光眼是世界上导致不可逆失明的主要原因。当眼压升高时

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility.

DOI：
10.1038/s41467-017-00837-5
发表时间：
2017-11-24
期刊：
Nature communications
影响因子：
16.6
作者：
Chintalapudi SR;Maria D;Di Wang X;Bailey JNC;NEIGHBORHOOD consortium;International Glaucoma Genetics consortium;Hysi PG;Wiggs JL;Williams RW;Jablonski MM
通讯作者：
Jablonski MM

Genetic pathways regulating glutamate levels in retinal Müller cells.

DOI：
10.1007/s11064-010-0277-1
发表时间：
2011-04
期刊：
NEUROCHEMICAL RESEARCH
影响因子：
4.4
作者：
Jablonski, Monica M.;Freeman, Natalie E.;Orr, William E.;Templeton, Justin P.;Lu, Lu;Williams, Robert W.;Geisert, Eldon E.
通讯作者：
Geisert, Eldon E.

The social life of neurons: synaptic communication deficits as a common denominator of autism, schizophrenia, and other cognitive disorders.

DOI：
10.1016/j.biopsych.2012.05.013
发表时间：
2012-08-01
期刊：
BIOLOGICAL PSYCHIATRY
影响因子：
10.6
作者：
Heck, Detlef H.;Lu, Lu
通讯作者：
Lu, Lu

Genetic and immunohistochemical analysis of HSPA5 in mouse and human retinas.

小鼠和人类视网膜中 HSPA5 的遗传和免疫组织化学分析。

DOI：
发表时间：
2016
期刊：
Molecular vision
影响因子：
2.2
作者：
Chintalapudi,SumanaR;Wang,XiaoFei;Li,Huiling;Lau,YinHChan;Williams,RobertW;Jablonski,MonicaM
通讯作者：
Jablonski,MonicaM

A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder.