The molecular basis of choroidal vascular development and RPE maintenance

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K11471
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Akishi Onishi 国立研究開発法人理化学研究所, 生命機能科学研究センター, 上級研究員 (70569102)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 神経網膜 / 網膜色素上皮 / 脈絡膜血管 / 加齢黄斑変性 / レチノイン酸

Outline of Final Research Achievements

Age-related macular degeneration (AMD) is characterized by degeneration in photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris, however, the etiology of AMD remains largely unknown. We found that Aldh1a1 KO mice show choroidal hypoplasia with the poor vasculature phenotype at the dorsal area from embryonic stage. Aldh1a1, an enzyme that synthesizes retinoic acids (RAs), is expressed in the embryonic dorsal neural retina, not in the RPE/choroid complex. We showed that RAs produced by Aldh1a1 in the neural retina directs dorsal choroidal vascular development via Sox9 upregulation in the dorsal RPE cells to enhance RPE-derived VEGF secretion. In the aged Aldh1a1 KO mouse, we found RPE degeneration and mislocalization of RPE markers. Also, these mice showed fragmentations of photoreceptors and attenuated REG b-wave response. The degeneration of RPE and photoreceptors in the aged Aldh1a1 KO mice are reminiscent of geographic atrophy, a characteristic lesion of dry AMD.

Free Research Field

分子発生学

Academic Significance and Societal Importance of the Research Achievements

Aldh1a1はマウスでは神経網膜背側部分に特異的に発現し、欠損マウスでは外側の脈絡膜毛細血管板に低形成を認めた解析結果は、神経網膜由来のレチノイン酸がRPEを挟んで更に外側の脈絡膜血管の形態形成に影響を及ぼす事を示す。これは、網膜発生学的に新規性が極めて高い研究成果であり、他の組織の血管形成機構の分子機序に関する新たな知見をもたらす。
また、前駆病変における遺伝子発現を同定した本研究成果は、中途失明原因の上位疾患である加齢黄斑変性の病態解明および先制医療（発症前予測・予防的治療）への応用が期待される事から医学的意義が高く、患者QOLの向上に寄与する事からも社会的にも大きな意義を持つ。