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

基本信息

  • 批准号:
    10359309
  • 负责人:
  • 金额:
    $ 9.97万
  • 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. We 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 our comprehension of the role of amyloid in glaucoma is in its infancy. Our current objective is to better understand molecular aspects of myocilin fibrilization, focused on the relevant olfactomedin (OLF) domain. Our multidisciplinary team 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 our understanding of glaucoma and its role in the TM, but will also extend our comprehension of the many other OLF domains, which are implicated broadly in physiology and diseases.
青光眼是全世界失明的主要原因(7000万患者),其医学管理方法是治疗

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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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:
    $ 9.97万
  • 项目类别:
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
  • 批准号:
    10789112
  • 财政年份:
    2011
  • 资助金额:
    $ 9.97万
  • 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:
    $ 9.97万
  • 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:
    $ 9.97万
  • 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:
    $ 9.97万
  • 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:
    $ 9.97万
  • 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:
    $ 9.97万
  • 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:
    $ 9.97万
  • 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:
    $ 9.97万
  • 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:
    $ 9.97万
  • 项目类别:

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