医学创新论坛第24期

时间：2024年 4月24日 9:30

地点: 首都医科大学科研北楼一层逸夫报告厅

主持人: 梅林

报告人: 李晓江

暨南大学粤港澳中枢神经再生研究院教授，广东省非人灵长类动物模型研究重点实验室主任，国家高层次引进人才，国家特聘专家。

美国Oregon Health Sciences University 博士及Johns Hopkins University博士后。自1996年以来，在美国Emory大学人类遗传学系任职并于2005晋升为终身正教授， 2007年起为杰出讲席教授。2008年获选教育部长江讲座教授，2010年入选国家高层次人才引进计划，2012-2016年在中国科学院遗传与发育生物学研究所利用CRISPR/Cas9等基因修饰技术制备重大疾病大动物模型。2019年全职加盟暨南大学，现任暨南大学粤港澳中枢神经再生研究院教授。

李晓江教授致力于研究早期神经系统发育、衰老与神经退行性疾病，利用转基因疾病动物（鼠，猪，猴）模型揭示与神经系统发育的重要基因和基因变异如何引起与衰老有关的蛋白构像异常与神经细胞死亡。研究成果发表于Cell、Nature等国际核心刊物250篇，研究论文累计引用率达到31430余次，H index 为 91。

Title: Use of monkey models to investigate brain diseases

Abstract:

Genetically modified animal models have been extensively utilized to explore the progression of age-related neurodegenerative conditions, including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) diseases, and Amyotrophic lateral sclerosis (ALS). These diseases share a common feature of age-related accumulation of misfolded proteins in the brain, a phenomenon replicated in various mouse models of neurodegenerative diseases. However, transgenic mouse models of AD, PD, and HD do not exhibit the pronounced neuronal loss or degeneration typically seen in patient brains. Discrepancies in pathology between transgenic mouse models and human brains may be attributed to species differences between small animals and humans. By utilizing CRISPR/Cas9 to express the disease genes in large animals such as monkeys, we can replicate typical neuropathological features in the brains of the larger animals. These results emphasize the significance of employing non-human primates to investigate the progression of significant brain disorders and their treatments.

Selected Papers:

1. Yin P, Guo X, Yang W, Yan S, Yang S, Zhao T, Sun Q, Liu Y, Li S, Li XJ. Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains. Acta Neuropathol. 2019 Jun;137(6):919-937.
2. Li B, Zhao H, Tu Z, Yang W, Han R, Wang L, Luo X, Pan M, Chen X, Zhang J, Xu H, Guo X, Yan S, Yin P, Zhao Z, Liu J, Luo Y, Li Y, Yang Z, Zhang B, Tan Z, Xu H, Jiang T, Jiang YH, Li S, Zhang YQ, Li XJ. CHD8 mutations increase gliogenesis to enlarge brain size in the nonhuman primate.Cell Discov. 2023 Mar 7;9(1):27.
3. Tu Z, Yan S, Han B, Li C, Liang W, Lin Y, Ding Y, Wei H, Wang L, Xu H, Ye J, Li B, Li S, Li XJ. Tauopathy promotes spinal cord-dependent production of toxic amyloid-beta in transgenic monkeys. Signal Transduct Target Ther.2023 Sep 22;8(1):358.   

报告人: 李世华

暨南大学粤港澳中枢再生研究院教授。江西医学院医学专业毕业，美国Johns Hopkins University大学博士后，1996-2019年在美国Emory大学工作并晋升为正教授。2019年6月作为第二层次高端人才全职加盟暨南大学。李世华教授是亨廷顿舞蹈病（HD）领域的世界著名专家，自1993年⼀直坚持用各种动物模型（小鼠, 猪, 猴) 对HD进行深⼊研究。李世华教授在建立及研究基因修饰小鼠模型的过程中发现小鼠模型不能表现选择性神经元死亡的典型病理变化，从而利用大动物疾病模型研究神经退行性疾病的病理机制。李世华教授参与建立了世界首例转基因HD猴模型 （2008年）、转基因HD猪模型 （2010年）、HD基因敲入猪模型 （2018年）及其它重要大动物疾病模型，在Nature、Cell、Science、Nature Medicine、Nature Genetics、Nature Neuroscience、Nature Biomedical Engineering、JCI、Neuron、PNAS等国际权威杂志发表论文近200篇。

Title: Huntington Disease Therapy by Targeting HTT

Abstract:

Huntington’s disease (HD) is caused by the abnormal expansion of CAG repeats in the huntingtin gene (HTT), leading to the production of the mutant huntingtin protein (mHTT) containing a polyglutamine sequence in its N-terminus. The pathogenic mechanisms driving HD are complex and not entirely understood. While mouse models carrying mutant HTT offer valuable insights into HD pathogenesis, many of these models do not exhibit the pronounced neurodegeneration typical of HD patients. We have established HD knock-in pigs that faithfully replicate selective neurodegeneration seen in HD. Employing gene therapy to eliminate the mutant gene in HD knock-in pigs can produce effective therapeutic outcomes. Additionally, we have developed a strategy to target mutant HTT using an intracellular antibody directed to the lysosome for degradation, demonstrating promising therapeutic effects on HD pathology.

Selected Papers:

1. Yan S, Tu Z, Liu Z, Fan N, Yang H, Yang S, Yang W, Zhao Y, Ouyang Z, Lai C, Yang H, Li L, Liu Q, Shi H, Xu G, Zhao H, Wei H, Pei Z, Li S, Lai L, Li XJ. A Huntingtin Knockin Pig Model Recapitulates Features of Selective Neurodegeneration in Huntington's Disease. 2018 May 3;173(4):989-1002.e13.

2. Yan S, Zheng X, Lin Y, Li C, Liu Z, Li J, Tu Z, Zhao Y, Huang C, Chen Y, Li J, Song X, Han B, Wang W, Liang W, Lai L, Li XJ, Li S.Cas9-mediated replacement of expanded CAG repeats in a pig model of Huntington's disease. Nat Biomed Eng. 2023 May;7(5):629-646.

3. Li C, Lin Y, Chen Y, Song X, Zheng X, Li J, He J, Chen X, Huang C, Wang W, Wu J, Wu J, Gao J, Tu Z, Li XJ, Yan S, Li S. A Specific Mini-Intrabody Mediates Lysosome Degradation of Mutant Huntingtin.Adv Sci (Weinh). 2023 Nov;10(31):e2301120.