Genetic Modulators of Glaucoma

青光眼的遗传调节剂

• 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
• 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

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.

青光眼是世界上不可逆失明的主要原因。同时升高眼内压（IOP） 是主要危险因素，残留神经节细胞（RGC）的损害和死亡是视野损失的基础。但是， 对这种疾病的理解是一个主要挑战，因为其遗传基础是异质的，它 代表由相交基因调节病理生理学引起的与年龄有关的疾病系列 网络。我们建议继续使用重组（RI）线的BXD（C57BL/6 x DBA/2J）系列 小鼠作为遗传参考面板（GRP）的工作，并将我们的工作与人类基因组范围的关联相结合 研究（GWAS），以发现和阐明遗传性​​异质性（ON）损害的遗传异质性。我们 最近在眼内压（IOP）调节中使用了这种联合方法。我们是 非常适合采取下一步并应用这种方法来定义RGC损伤的细胞靶标 和死亡。我们建议揭示与损害和发现有关的青光眼相关的表型多样性 与IOP调制共享的共同基础机制。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，以保护患者的永久健康 青光眼的风险。我们的总体目标是确定新的基因产品和相关机制，导致 使用多维遗传分析，跨物种比较（小鼠，，小鼠， 大鼠和人）以及使用新型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 - 尾型（例如IOP升高和损坏）的过程是 跨物种共享，物种比较可以发现共同的潜在机制，并且 有效测试靶向青光眼治疗。在当前的调查中，我们执行系统 分析损害和另一种物种 - rat。我们将挖掘IOP和ON的广泛数据库 我们正在为五个年龄段的70多个BXD菌株产生的损害，目的是定义 青光眼的新模型。该提案的总体优势是尖端系统的结合 遗传学方法，青光眼表型的物种比较以及一个强大的跨学科团队 包括在系统遗传学，青光眼，人类和大鼠中具有丰富经验的研究人员， 和高级计算方法。为了检验我们的假设，我们将执行以下分布研究：1） 确定对损伤调节的第12染色体上的候选基因； 2）确定IOP的调制是否 和/或损害在啮齿动物物种之间共享； 3）确定新型的赞助青光眼模型 通过对100或更多BXD菌株的扩大BXD GRP的全面分析。结果 这些研究将定义基于青光眼相关表型的新基因和分子网络 并提供独特的青光眼模型，用于将来分析。这些结果有望从根本上 推进青光眼疾病机制的领域，并使有针对性的治疗发展。

项目成果

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

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 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.

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

• DOI: 10.3389/fnbeh.2015.00171
• 发表时间: 2015
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3
• 作者: Ashbrook DG;Williams RW;Lu L;Hager R
• 通讯作者: Hager R

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。

• 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