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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转失明的主要原因。当眼压（IOP）升高时视网膜神经节细胞 (RGC) 的损伤和死亡是视野丧失的主要危险因素。然而，一个彻底了解这种疾病是一项重大挑战，因为它的遗传基础是异质的，而且代表由交叉基因调节的病理生理学引起的一系列与年龄相关的疾病网络。我们建议继续使用 BXD (C57BL/6 x DBA/2J) 重组自交 (RI) 系家族小鼠作为遗传参考组（GRP）并将我们的工作与人类基因组广泛关联相结合研究（GWAS），揭示并阐明视神经（ON）损伤背后的遗传异质性。我们最近使用这种组合方法调节眼内压（IOP）取得了成功。我们是非常有能力采取下一步并应用这种方法来定义 RGC 损伤的细胞目标和死亡。我们建议揭示青光眼相关视神经损伤的表型多样性并揭示与 IOP 调制共享的共同底层机制。我们的长期研究目标是确定疾病机制并开发神经保护疗法，以保护患者的视网膜健康青光眼的风险。我们的总体目标是识别新的基因产物和相关机制，从而导致使用多维遗传分析、跨物种比较（小鼠、大鼠和人类）并使用新型小鼠青光眼模型进行验证。我们的中心假设是分子导致青光眼相关内表型的过程，例如 IOP 升高和 ON 损伤跨物种共享，物种比较可以揭示共同的潜在机制，并且靶向青光眼治疗的有效测试。在当前的调查中，我们进行了系统的调查 ON损伤的分析，以及一个额外的物种——大鼠。我们将挖掘 IOP 和 ON 的广泛数据库我们对五个年龄段的 70 多种 BXD 菌株产生的损害，目的是定义青光眼的新模型。该提案的整体优势在于尖端系统的结合遗传学方法、青光眼表型的物种比较以及强大的跨学科团队包括在系统遗传学、青光眼、人类和大鼠 GWAS 方面拥有丰富经验的研究人员，和先进的计算方法。为了检验我们的假设，我们将进行以下三项研究：1) 确定 12 号染色体上调节 ON 损伤的候选基因； 2) 确定IOP是否调制和/或 ON 损伤在啮齿类动物物种之间共有； 3) 识别新型自发性青光眼模型通过对我们扩大的100个或更多BXD菌株的BXD GRP进行综合分析。结果这些研究将定义青光眼相关表型背后的新基因和分子网络并提供独特的青光眼模型以供将来分析。这些结果预计将从根本上推进青光眼疾病机制领域的发展并实现有针对性的治疗开发。

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.