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

• 批准号: 10018872
• 负责人: GEOFFREY A CHANG
• 金额: $ 19.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/10018872
• 关键词: Affinity; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antibodies; Binding; Biological Assay; Biophysics; Birth; Cataract; Characteristics; Chemical Structure; Chemicals; Chimeric Proteins; Chromosome 21; Chromosomes; Cleaved cell; Clinical; Collaborations; Communities; Congenital chromosomal disease; Deposition; Development; Devices; Disease; Disease Progression; Down Syndrome; Epithelial; Epithelium; 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; 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

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.

项目概要/摘要 唐氏综合症 (DS) 是最常见的染色体疾病，每 700 名新生儿中就有 1 人患有唐氏综合症。 值得庆幸的是，这是导致智力障碍的主要原因。 随后出现了一些与阿尔茨海默病 (AD) 相同的健康问题。 由正常第 21 对染色体（21 号染色体）增加一条染色体引起。 导致 AD 的基因；最突出的淀粉样前体蛋白 (APP)，它被切割形成不同的形式 AD 大脑中 A 斑块的积累是其定义的病理学之一，A 也是其特征之一。 患有 DS 的人眼睛中存在多种眼部异常，包括白内障，发生率要高得多。 DS 患者从年轻时开始出现的频率这些眼部疾病与 A 有关，这可能会影响 A。 引起晶状体上皮层的氧化应激和变性。 为了仔细了解 A 对眼睛的贡献和作用，我们建议采用一种强大的技术 用于发现可用作构象异构体特异性探针的大量纳米抗体 (Nbs) 的平台 研究 A 在眼睛（视网膜和晶状体组织）中的组织学分布将使我们能够 识别被忽视和可能罕见的 A 寡聚构象异构体，这对于区分可能很重要 DS 眼睛中发现的沉积物，也许可以为 AD 提供一些重要的见解。 此外，我们的一些 Nbs 可能会产生一些重要的见解。 隔离并溶解 A 的某些低聚物和聚集体，从而实现新型药物的潜在开发 我们的具体目标是：(1) 发现、生产和使用治疗方法。 针对 A 蛋白构象异构体种类的不同构象验证 Nbs 并 (2) 测试和验证该面板 使用 AD 小鼠模型的眼组织和晶状体来分析 Nbs，这些 Nbs 将是有价值的试剂。 对于那些学习 DS 和 AD 的人来说。