Characterization of purified myocilin : glaucoma as a protein misfolding disease DEIA Supplement

纯化肌纤蛋白的表征:青光眼作为一种蛋白质错误折叠疾病 DEIA 补充

基本信息

  • 批准号:
    10789112
  • 负责人:
  • 金额:
    $ 38.46万
  • 依托单位:
  • 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:
    2011-03-01 至 2026-02-28
  • 项目状态:
    未结题

项目摘要

Glaucoma, a leading cause of blindness worldwide (70 million patients), is managed medically by treating the symptom of increased intraocular pressure (IOP), but 10% of patients still go blind. IOP is controlled in the anterior segment of the eye, which contains the trabecular meshwork (TM) extracellular matrix, the anatomical pathway for drainage of aqueous humor fluid. The TM tissue is diseased in most forms of glaucoma; loss of TM homeostasis leads to elevated IOP. Hereditary open angle glaucoma, affecting ~3 million young patients, is caused by mutations in myocilin, a protein highly expressed in the TM. Since 3/2011, studies funded from R01EY021205 have changed the paradigm for anti-glaucoma therapeutics by laying the molecular foundation for approaches that target the disease process, which are now being pursued in academia and industry. Studies from R01EY021205 have clarified molecular details of the toxic gain-of-function pathogenic mechanism in which mutant myocilin accumulates in the endoplasmic reticulum (ER) of TM cells, leading to TM cell death and an accelerated timeline for vision loss. Studies from R01EY021205 (a) contributed fundamental knowledge of myocilin structure, (b) discovered a counter-productive interaction between myocilin and the ER-resident Hsp90 chaperone Grp94, and (c) characterized myocilin misfolding as amyloid. Wild-type and many different myocilin variants harbor a misfolding propensity; thus, proteostasis issues identified in familial myocilin-associated glaucoma are likely at play in many more patients. Amyloid formation by myocilin places glaucoma alongside more well-studied amyloid diseases like Alzheimer and SOD-1 dependent amyotrophic lateral sclerosis, yet comprehension of the role of amyloid in glaucoma is in its infancy. The current objective is to better understand molecular aspects of myocilin fibrilization, focused on the relevant olfactomedin (OLF) domain. The multidisciplinary team led by Raquel Lieberman will (a) clarify initiation of aggregation by studying solution structures of wild-type and selected OLF variants, as well as corresponding multi-length scale dynamics, using hydrogen-deuterium exchange mass spectrometry and nuclear magnetic resonance (NMR) structure and relaxation methods (Wade Van Horn, Co- I) (b) compare the end-point structures of selected OLF aggregates to known amyloids by solid state NMR (Anant Paravastu, Co-I) and evaluate cytotoxicity of intermediate aggregates and (c) evaluate common allele full-length myocilin variants for experimental hallmarks of pathogenicity. The expected outcome is a better understanding of the myocilin misfolding process at the molecular level, including molecular determinants of pathogenicity, to enable novel modalities for studying, diagnosing, and treating myocilin-associated glaucoma. More broadly, continued structure/dysfunction studies of myocilin will not only contribute to an understanding of glaucoma and its role in the TM, but will also extend comprehension of the many other OLF domains, which are implicated broadly in physiology and diseases.
青光眼是全球范围内导致失明的主要原因(7000万患者), 眼内压(IOP)升高的症状,但仍有10%的患者失明。眼压控制在 眼前节,其中含有小梁网(TM)细胞外基质,解剖 水状体液的排出途径。在大多数形式的青光眼中,TM组织是患病的; TM组织的丧失导致青光眼。 TM稳态导致IOP升高。遗传性开角型青光眼,影响约300万年轻患者, 是由肌球蛋白突变引起的,肌球蛋白是一种在TM中高度表达的蛋白质。自2011年3月以来, R 01 EY 021205通过奠定分子基础改变了抗青光眼治疗的范式 目前学术界和工业界都在寻求针对疾病过程的方法。 来自R 01 EY 021205的研究阐明了毒性功能获得性致病性 突变型myocilin在TM细胞的内质网(ER)中积累,导致 TM细胞死亡和视力丧失的加速时间轴。来自R 01 EY 021205(a)的研究 肌球蛋白结构的基础知识,(B)发现肌球蛋白与肌球蛋白之间的反作用相互作用 和ER驻留的Hsp 90伴侣Grp 94,和(c)表征为淀粉样蛋白的肌球蛋白错误折叠。野生型 并且许多不同的肌球蛋白变体具有错误折叠的倾向;因此, 家族性肌青霉素相关青光眼可能在更多的患者中起作用。 由肌球蛋白引起的淀粉样蛋白形成将青光眼与淀粉样蛋白疾病并列, 阿尔茨海默病和SOD-1依赖性肌萎缩侧索硬化症,但对淀粉样蛋白在 青光眼还处于婴儿期。目前的目标是更好地了解分子方面的myocilin 原纤维化,集中在相关的嗅觉调节蛋白(OLF)结构域。拉奎尔领导的多学科团队 Lieberman将(a)通过研究野生型和选择的OLF的溶液结构来阐明聚集的起始 变体,以及相应的多长度尺度动力学,使用氢-氘交换质量 光谱法和核磁共振(NMR)结构和弛豫方法(Wade范霍恩,Co- I)(B)通过固态NMR比较所选OLF聚集体与已知淀粉样蛋白的终点结构 (Anant Paravastu,Co-I)并评价中间聚集体的细胞毒性和(c)评价共同等位基因 全长myocilin变体用于致病性的实验标志。预期的结果是更好的 在分子水平上理解肌球蛋白的错误折叠过程,包括 致病性,以使新的方式研究,诊断和治疗肌球蛋白相关性青光眼。 更广泛地说,持续的肌钙蛋白结构/功能障碍研究不仅有助于理解 青光眼及其在TM中的作用,但也将扩展对许多其他OLF领域的理解, 与生理学和疾病有着广泛的联系。

项目成果

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Raquel L Lieberman其他文献

Raquel L Lieberman的其他文献

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{{ truncateString('Raquel L Lieberman', 18)}}的其他基金

Characterization of purified myocilin: glaucoma as a protein misfolding disease
纯化肌纤蛋白的表征:青光眼作为一种蛋白质错误折叠疾病
  • 批准号:
    10723134
  • 财政年份:
    2011
  • 资助金额:
    $ 38.46万
  • 项目类别:
Characterization of purified myocilin: glaucoma as a protein misfolding disease
纯化肌纤蛋白的表征:青光眼作为一种蛋白质错误折叠疾病
  • 批准号:
    8616070
  • 财政年份:
    2011
  • 资助金额:
    $ 38.46万
  • 项目类别:
Characterization of purified myocilin: glaucoma as a protein misfolding disease
纯化肌纤蛋白的表征:青光眼作为一种蛋白质错误折叠疾病
  • 批准号:
    10357759
  • 财政年份:
    2011
  • 资助金额:
    $ 38.46万
  • 项目类别:
Characterization of purified myocilin: glaucoma as a protein misfolding disease
纯化肌纤蛋白的表征:青光眼作为一种蛋白质错误折叠疾病
  • 批准号:
    9239535
  • 财政年份:
    2011
  • 资助金额:
    $ 38.46万
  • 项目类别:
Characterization of purified myocilin: glaucoma as a protein misfolding disease
纯化肌纤蛋白的表征:青光眼作为一种蛋白质错误折叠疾病
  • 批准号:
    10052403
  • 财政年份:
    2011
  • 资助金额:
    $ 38.46万
  • 项目类别:
Characterization of purified myocilin: glaucoma as a protein misfolding disease
纯化肌纤蛋白的表征:青光眼作为一种蛋白质错误折叠疾病
  • 批准号:
    8232001
  • 财政年份:
    2011
  • 资助金额:
    $ 38.46万
  • 项目类别:
Request for Supplement to Promote Diversity in Health Related Research
请求补充以促进健康相关研究的多样性
  • 批准号:
    10359309
  • 财政年份:
    2011
  • 资助金额:
    $ 38.46万
  • 项目类别:
CHARACTERIZATION OF PURIFIED MYOCILIN: INSIGHT INTO GLAUCOMA
纯化肌青蛋白的表征:洞察青光眼
  • 批准号:
    10622963
  • 财政年份:
    2011
  • 资助金额:
    $ 38.46万
  • 项目类别:
Characterization of purified myocilin: glaucoma as a protein misfolding disease
纯化肌纤蛋白的表征:青光眼作为一种蛋白质错误折叠疾病
  • 批准号:
    8420505
  • 财政年份:
    2011
  • 资助金额:
    $ 38.46万
  • 项目类别:
Characterization of purified myocilin: glaucoma as a protein misfolding disease
纯化肌纤蛋白的表征:青光眼作为一种蛋白质错误折叠疾病
  • 批准号:
    10614924
  • 财政年份:
    2011
  • 资助金额:
    $ 38.46万
  • 项目类别:

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