在 莎朗·埃克尔斯·斯蒂尔转化医学中心 在犹他大学 John A. Moran Eye Center explains why people carrying a block of genetic variants strongly associated with the development of age-related macular degeneration (AMD) may develop the disease and identifies a potential therapeutic pathway for slowing or even reversing disease progression.
AMD is a major cause of irreversible blindness worldwide and the leading cause of blindness for Americans aged 55 and over. Following more than 15 years of research that has employed an extensive repository of donated human ocular tissues, scientists found that HtrA1 protein normally increases with age in the eye at the retinal pigmented epithelium (RPE)-Bruch’s membrane interface, 大发娱乐维持这个区域的正常功能. The RPE is a cell layer that delivers nutrients to and removes waste from the retina’s light-sensitive photoreceptor cells.
These new data show this is not the case in individuals with AMD-associated risk variants located on chromosome 10. 这些变异被发现损害了基因的表达 HTRA1 gene by the RPE, resulting in an approximately 50 percent reduction of HtrA1 protein levels at the RPE-Bruch’s membrane interface during aging. The failure to produce adequate levels of HtrA1 protein disrupts this key region of the eye and is associated with AMD-associated pathologies, 包括异常沉积物的沉积和异常血管的发育.
这些发现来自SCTM执行主任的实验室 Gregory S. Hageman, PhD, represent the first explanation of the essential role of HtrA1 in maintaining ocular health and contradict literature previously published by others. 它们有望为10号染色体定向AMD的新疗法的发展大发娱乐提供信息.
这些研究数据将于2021年7月19日当周出现在 美国国家科学院院刊 (PNAS): “染色体10q26驱动的年龄相关性黄斑变性与维生素d水平降低有关 HTRA1 人视网膜色素上皮."
“大发娱乐能够得出这些令人兴奋的结果，要感谢大发娱乐的眼睛捐赠者和他们的家人. 大发娱乐非常感激他们送给大发娱乐的珍贵礼物."
Lead author Brandi L. 威廉姆斯博士说，她的团队发现，维生素d水平显著降低 HTRA1 messenger ribonucleic acid (mRNA) in the RPE and secreted HtrA1 protein at the RPE-Bruch’s membrane interface. Reduced HTRA1 发现表达具有风险等位基因特异性, 但只在RPE中，而不是在视网膜或脉络膜中. Notably, 研究小组还将与amd相关的10号染色体的一个大的遗传区域缩小到一个小得多的因果区域, 是什么导致了 HTRA1.
"Our findings are significant because they suggest that HtrA1 normally maintains the integrity of the RPE-Bruch’s membrane interface during the aging process by, in essence, turning over extracellular material and preventing abnormal deposits—including basal laminar deposits—from accumulating between the RPE and Bruch’s membrane," said Williams. "Earlier unpublished SCTM studies documented a significant association between chromosome 10 and the formation of basal laminar deposits. Viewing HtrA1 as protective runs contrary to what one might expect because elevation of HtrA1 protein is thought to be a contributing factor in some diseases such as osteoarthritis."
访问超过8个独特的存储库,000 pairs of donated human eyes was essential to this study since there are no animal models that accurately mimic the biology of chromosome 10-directed AMD. 这个关键资源允许SCTM团队进行比较 HTRA1 来自有或没有10号染色体相关风险基因型的供体的眼睛中的表达.
“大发娱乐能够得出这些令人兴奋的结果，要感谢大发娱乐的眼睛捐赠者和他们的家人," said Hageman. “大发娱乐非常感谢他们珍贵的礼物."
The SCTM team conducted a number of difficult and time-consuming experiments to reach their groundbreaking conclusions, which contradict previously published literature reporting either no difference or elevated levels of HtrA1 in human ocular tissues or blood. Hageman pointed out that "those particular studies employed too few samples and the analyses were performed using neural retina and white blood cells, 而不是RPE-Bruch膜, 哪里是AMD发病的主要部位."
"Unfortunately, data generated by prior studies have led to the development and testing of therapies—some of which are currently in human clinical trials—designed to reduce overall levels of HtrA1, 这种方法可能会加剧AMD的进展," said Hageman. “大发娱乐的团队一直孜孜不倦地追求准确性, 进行了许多极其困难的实验来获得这些数据. 他们年复一年地坚持下去, 我对这个天才团队的数据和科学敏锐度感到无比兴奋."
“这些数据对整个领域和患有这种毁灭性疾病的患者都很重要, especially in light of developing therapeutic technologies to correct genes by excising the defected region and repairing it."
具有广泛影响的方法
威廉姆斯说，这项研究将产生广泛的影响.
“这些数据对整个领域和患有这种毁灭性疾病的患者都很重要," she said, "especially in light of developing therapeutic technologies to correct genes by excising the defected region and repairing it."
SCTM科学家和临床医生现在专注于开发一种治疗10号染色体定向AMD的方法. They have also developed a potential therapy for individuals at risk for AMD due to abnormal genes lying on chromosome 1. 1号染色体和10号染色体加在一起，占患AMD遗传风险的50%以上.
这是Hageman在PNAS上发表的第二篇与AMD主要遗传基础相关的文章. In 2005, a landmark paper revealed that genetic variants and haplotypes in the Complement Factor H and related genes on chromosome 1 predispose individuals to AMD.
"When Dr. 哈格曼在近30年前开始了他的amd相关研究, 他是一名海洋生物学家，他决定改变方向，在这个可怕的时候研究AMD, 致盲疾病被简单地认为是一种任何人都无能为力的疾病," said Randall J Olson, MD莫兰眼科中心首席执行官兼眼科和视觉科学杰出教授. "He didn’t accept that. I didn’t accept that. Thus, we created the SCTM as a unique academic model designed to quickly turn discoveries into therapies through partnerships with philanthropists and industry as well as national and international scientific collaborators."
A major gene expression study conducted as part of a research and development collaboration with Allergan in 2014 employed various ocular tissues and blood cells from over 700 donors and patients, generated about 9.20亿数据点，并揭示了与基因导向AMD生物学相关的新见解.
“很明显，大发娱乐的方法是有效的，”奥尔森说. Hageman and his team have greatly advanced and continue to advance our knowledge about AMD and to develop treatments for it."
SCTM的作者团队是：Brandi L. Williams, Nathan A. Seager, Jamie D. Gardiner, Chris M. Pappas, Monica C. 克罗宁，克里斯蒂娜·阿马特·迪·圣菲利波，罗伯特·A. 刘瑾，安施塔特，马克A. Toso, Lisa Nichols, Timothy J. Parnell, Jacqueline R. Eve, Paul L. Bartel, Moussa A. Zouache, Burt T. Richards, and Gregory S. Hageman.
这项研究得到了美国国立卫生研究院（R01 EY014800）的部分资助, R24 EY017404); charitable donations made to the Sharon Eccles Steele Center for Translational Medicine; and an unrestricted grant from Research to Prevent Blindness, New York, NY, 眼科和视觉科学系, University of Utah.
About the John A. Moran Eye Center
The John A. Moran Eye Center at the University of Utah serves as the largest ophthalmology clinical care and research facility in the Mountain West, 拥有60多名教职员工和10个卫星诊所. 医生在所有眼科专科大发娱乐提供全面的护理, 这使得莫兰眼科中心成为治疗超过145例复杂病例的主要转诊中心,000名病人就诊，约7,000 surgeries annually. 莫兰支持15个研究实验室, and its Sharon Eccles Steele Center for Translational Medicine works to turn lab discoveries into therapies quickly through public-private partnerships. 首席执行官兼眼科和视觉科学杰出教授兰德尔·J·奥尔森, MD, leads more than 500 employees working to achieve the Moran Eye Center’s vision that no person with a blinding condition, eye disease, 或者视力障碍应该没有希望, understanding, and treatment.