Down syndrome, early cataracts, eye diseases, and beta-amyloid conformers

唐氏综合症、早期白内障、眼部疾病和 β-淀粉样蛋白构象异构体

基本信息

批准号：
9893680
负责人：
GEOFFREY A CHANG
金额：
$ 23.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893680
关键词：
Affinity Age Alzheimer&apos s Disease Amyloid Amyloid Proteins Amyloid beta-Protein Amyloid beta-Protein Precursor Antibodies Binding Biological Assay Biophysics Birth Brain Diseases Cataract Characteristics Chemical Structure Chemicals Chimeric Proteins Chromosomes Chromosomes, Human, Pair 21 Cleaved cell Clinical Collaborations Communities Congenital chromosomal disease Deposition Development Devices Disease Disease Progression Down Syndrome Epithelial Epitopes Evolution Eye Eye diseases Fluorescent Probes Frequencies Future Genes Goals Health Histologic Human Image Immune Immunohistochemistry In Vitro Individual Intellectual functioning disability Investigation Kinetics Letters Libraries Link Longevity Measures Methods Molecular Conformation Mus Nature Ophthalmologist Oxidative Stress Pathology Play Proteins Quaternary Protein Structure Reagent Reporting Research Resources Retina Retinal Role Senile Plaques Specificity Stains Structure Technology Testing Therapeutic Tissue Sample Tissues Validation conformer early onset imager improved insight lens molecular recognition monomer mouse model nanobodies novel novel therapeutics prevent protein oligomer

Affinity Age Alzheimer&apos s Disease Amyloid Amyloid Proteins Amyloid beta-Protein Amyloid beta-Protein Precursor Antibodies Binding Biological Assay Biophysics Birth Brain Diseases Cataract Characteristics Chemical Structure Chemicals Chimeric Proteins Chromosomes Chromosomes, Human, Pair 21 Cleaved cell Clinical Collaborations Communities Congenital chromosomal disease Deposition Development Devices Disease Disease Progression Down Syndrome Epithelial Epitopes Evolution Eye Eye diseases Fluorescent Probes Frequencies Future Genes Goals Health Histologic Human Image Immune Immunohistochemistry In Vitro Individual Intellectual functioning disability Investigation Kinetics Letters Libraries Link Longevity Measures Methods Molecular Conformation Mus Nature Ophthalmologist Oxidative Stress Pathology Play Proteins Quaternary Protein Structure Reagent Reporting Research Resources Retina Retinal Role Senile Plaques Specificity Stains Structure Technology Testing Therapeutic Tissue Sample Tissues Validation conformer early onset imager improved insight lens molecular recognition monomer mouse model nanobodies novel novel therapeutics prevent protein oligomer

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项目摘要

PROJECT SUMMARY/ABSTRACT Down syndrome (DS) is the most common chromosomal disorder with an occurrence of 1 in 700 births. It is, by far, the leading known cause of intellectual disability. The longevity of DS people has thankfully increased and several health issues have subsequently emerged, sharing commonality with Alzheimer’s disease (AD). DS is caused by an additional chromosome to the normal 21st pair (Trisomy 21). Chromosome 21 encodes several genes contributing to AD; most notably amyloid precursor protein (APP), which is cleaved to form different forms of beta-amyloid (A). Accumulation of A plaques in the AD brain is one its defining pathologies and A is also present in the eyes of people with DS. Multiple ocular anomalies, including cataracts, occur at a much higher frequency starting at younger ages for people with DS. These eye disorders are associated with A, which can cause oxidative stress and degeneration in the lens epithelial layer. To carefully understand the contribution and role of A in the eye, we propose to adapt a powerful technology platform for the discovery of a large panel of nanobodies (Nbs) that can be used as conformer-specific probes to investigate the histological distribution of A in the eye (retina and lens tissue). These Nbs would allow us to identify overlooked and potentially rare A oligomeric conformers, which could be important to differentiate deposits found in DS eyes, perhaps yielding some important insights for AD. Further, some of our Nbs may sequester and dissolve certain oligomers and aggregates of A, enabling the potential development of novel therapeutics delivered into the eyes of those with DS and AD. Our specific aims are: (1) discover, produce, and validate Nbs against different conformations of A protein conformer species and (2) test and validate this panel of Nbs using eye tissue and lens from AD mouse models recapitulating DS. These Nbs will be valuable reagents for those studying DS and AD.

项目摘要/摘要唐氏综合症（DS）是最常见的染色体疾病，发生在700名分娩中有1例。它是远方，是智力残疾的主要已知原因。值得庆幸的是，DS人的寿命增加了，随后出现了一些健康问题，与阿尔茨海默氏病（AD）共同。 DS是由正常第21对（三体第21对）的额外染色体引起。染色体21编码几个促成AD的基因；最值得注意的是淀粉样蛋白前体蛋白（APP），该蛋白被切割成不同形式 β-淀粉样蛋白（A）。广告大脑中A斑块的积累是其定义的病理，A也是出现在患有DS的人的眼中。多个眼异常，包括白内障，发生在更高的地方 DS患者的年轻年龄从年轻人开始。这些眼睛障碍与A相关，可以导致晶状体上皮层的氧化应激和变性。要仔细了解A在眼中的贡献和作用，我们建议适应强大的技术发现大型纳米型（NB）的平台，可以用作特定于构象异构的问题研究眼睛中A的组织学分布（视网膜和镜头组织）。这些NB将使我们能够识别被忽视的且可能罕见的A低聚物构象体，这对于区分可能很重要在DS眼中发现的沉积物，也许可以为AD提供一些重要的见解。此外，我们的一些NB可能隔离并溶解A的某些低聚物和聚集体，从而实现了新型的潜在发展治疗药物传递到了DS和AD的人的眼中。我们的具体目的是：（1）发现，生产和验证NBS与A蛋白质构象物种的不同考虑，（2）测试和验证该图使用眼组织和AD小鼠模型的镜头概括DS的NB。这些NB将是有价值的试剂对于那些学习DS和AD的人。