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
- 来源:
- 关键词:AcademiaAccelerationAffectAllelesAlzheimer&aposs DiseaseAmyloidAmyloidosisAmyotrophic Lateral SclerosisAnatomyAnterior eyeball segment structureAqueous HumorBlindnessCell DeathCellsComprehensionDeuteriumDiagnosisDiseaseDrainage procedureEndoplasmic ReticulumExtracellular MatrixExtracellular Matrix ProteinsEyeEye diseasesFoundationsFunctional disorderFundingGlaucomaGoalsHomeostasisHornsHydrogenIndustryInheritedKnowledgeLeadLengthLiquid substanceMass Spectrum AnalysisMedicalMethodsModalityMolecularMolecular ChaperonesMutationNerve DegenerationNuclear Magnetic ResonanceOpen-Angle GlaucomaOutcomePathogenesisPathogenicityPathway interactionsPatientsPhysiologic Intraocular PressurePhysiologyPlayProcessProteinsRelaxationRetinaRoleStructureTherapeuticTissuesTrabecular meshwork structureVariantamyloid formationblindcytotoxicityearly onsetgain of functioninfancymultidisciplinarymutantmyocilinnovelnovel therapeuticsolfactomedinpressureprotein misfoldingproteostasissolid state nuclear magnetic resonancesuperoxide dismutase 1symptom treatmenttimeline
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(0)
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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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