• 1. We explore the genetic and epigenetic regulation of cortical development in Down syndrome and autism, especially on neurogenesis, neuronal migration, and synaptic formation.
• 2. We study the modulation of nociceptive transmission and perception in Down syndrome.
• 3. We explore the mechanisms of music therapy in autism.
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国家自然基金面上项目82271203: DNMT3L改变组蛋白甲基化增强谷氨酸受体GRIN2B、GRIA2表达致自闭症样行为的表观遗传机制研究

我们在Dnmt3l大脑皮层条件过表达小鼠观察到自闭症样行为、谷氨酸受体表达增高和突触棘密度增加等表型, 并发现DNMT3L与组蛋白甲基转移酶CARM1及EHMT2结合且在Grin2b基因启动子区富集，因此提出假说：过量表达的Dnmt3l通过结合组蛋白精氨酸甲基转移酶CARM1及作为辅助因子的EHMT2形成蛋白复合体，增加谷氨酸受体基因启动子区H3R17me2a的富集并征募转录激活因子，同时减少可用作赖氨酸甲基转移酶的EHMT2，减少H3K9m2的富集，从而增加谷氨酸受体基因表达，进而导致突触活动增强，神经元兴奋性增高及自闭症样行为。为验证上述假说，我们拟利用Dnmt3l+（Emx1-cre）条件过表达及Dnmt3l-（Emx1-cre）条件敲除小鼠，研究DNMT3L通过结合CARM1及EHMT2增加谷氨酸受体Grin2b及Gria2表达，增加神经兴奋性，引起自闭症样行为的分子机制。

国家自然基金面上项目81771229: DNA甲基化转移酶DNMT3L调控突触蛋白基因表达及其在唐氏综合征大脑皮层发育异常中的作用机制

智能障碍是唐氏综合征最显著的神经表型；关于突触可塑性的研究是理解其发病机制的关键。最近我们观察到病人神经细胞基因组广泛的DNA甲基化增高现象； 21号染色体基因DNMT3L过表达能改变某些突触蛋白（PSD95、APP）的表达。因此我们认为过量表达的DNMT3L通过激活DNMT3A及DNMT3B使基因组整体的DNA甲基化增高，或者通过抑制组蛋白甲基转移酶使活跃基因转录相关组蛋白的甲基化降低，从而改变相关下游基因（APP、TP53、DLG4等）的表达，进而导致包括突触可塑性及学习记忆功能降低在内的某些唐氏综合征表型。为此在本项目中，我们拟制做三拷贝DNMT3L神经细胞及动物模型，检测基因组甲基化及基因表达，寻找DNMT3L的靶基因，探讨DNMT3L引发靶基因甲基化增高及基因表达改变的分子机制，观察DNMT3L过表达对神经发育表型的影响，证明上述假说的成立，为其早期诊治提供理论及实验依据。

国家自然基金面上项目82271203，DNMT3L改变组蛋白甲基化增强谷氨酸受体GRIN2B、GRIA2表达致自闭症样行为的表观遗传机制研究

，52万人民币，负责人

国家自然基金面上项目81771229，DNA甲基化转移酶DNMT3L调控突触蛋白基因表达及其在唐氏综合征大脑皮层发育异常中的作用机制

，80万人民币，负责人

1.        Lu J., McCarter M., Lian G., Esposito G., Capoccia E., Sheen V. Globalhypermethylation in fetal cortex of Down syndrome due to DNMT3L overexpression.Hum. Mol. Genet. 2016, 25:1714-1727. PMID: 26911678. IF=5.34

2.        Esposito G., Sarnelli G., CapocciaE., Cirillo C., Pesce M., Lu J.,Calì G., Cuomo R., Steardo L. Autologous transplantation of intestine-isolatedglia cells improves neuropathology and restores cognitive deficits in βamyloid-induced neurodegeneration. Sci.Rep. 2016, 6:22605. PMID: 26940982.

3.        Lian G.,Dettenhofer M., Lu J.,Downing M., Chenn A., Wong T., SheenV. FilaminA and Formin2 dependent endocytosis regulates proliferationvia the canonical Wnt pathway. Development.2016, 143:4509-4520. PMID: 27789627.

4.        HuJ.#, Lu J.#, GoyalA., Wong T., Lian G., Zhang J., Hecht J.L., Feng Y., Sheen V.L. Opposing FlnA and FlnB interactions regulateRhoA activation in guiding dynamic actin stress fiber formation and cellspreading. Hum. Mol. Genet.  2017，26:1294-1304. PMID: 28175289. 5.34+# Theseauthors contribute equally to the work. IF=5.34

5.        Sarnelli G.,Seguella. L, Pesce. M, Lu J.,Gigli S., Bruzzese E., Lattanzi R., D'Alessandro A., Cuomo R., Steardo L., Esposito G. HIV-1 Tat-induced diarrheais improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing theactivation of enteric glia. JNeuroinflammation. 2018, 15:94. PMID:29573741.

6.        Lian G., WongT., Lu J., HuJ., Zhang J., Sheen V.L. Cytoskeletal Associated Filamin A and RhoA AffectNeural Progenitor Specification During Mitosis. Cereb Cortex. 2019， 29(3):1280-1290. PMID:29462287.

7.        Adnan A., Rakha A., Ameen F., Alarfaj A.A., Almansob A., Wang C.C., LuJ.*, Xing J*. Genetic structure and forensic characteristics ofSaraiki population from Southern Punjab, Pakistan, revealed by 20 Y-chromosomalSTRs. Int J Legal Med. 2020，134(3): 977-979.  PMID:31392415. IF=2.222

8.        Adnan A.,Kasimu K., Rakha A., He G., Yang T., Wang C.C., Lu J.*, Xing J*. Comprehensivegenetic structure analysis of Han population from Dalian City revealed by 20Y-STRs. Mol Genet Genomic Med. 2020，8(3): e1149. PMID: 31989793. IF=2.183

9.        Adnan A.,Rakha A., Nazir S., Rehman Z., Lu J.*, Xing J.* Geneticcharacterization of 15 autosomal STRs in the interior Sindhi population ofPakistan and their phylogenetic relationship with other populations. Int JImmunogenet. 2020， 47(2): 149-157. PMID: 31657139. IF=1.130

10.    Esposito G., Pesce M., Seguella L., SanseverinoW., Lu J.,Sarnelli G. Can theEnteric Nervous System Be an Alternative Entrance Door in SARS-CoV2Neuroinvasion? Brain Behav Immun. 2020,S0889-1591(20)30644-9. PMID: 32335192

11.    Esposito G., Pesce M.,Seguella L., Sanseverino W., Lu J., Corpetti C., Sarnelli G. The Potential of Cannabidiol in the COVID-19 Pandemic: A HypothesisLetter. Br J Pharmacol. 2020Jun 10, PMID: 32519753

12.    Sarnelli G., Pesce M., Seguella L., Lu J., Efficie E.,Tack J., Elisa De Palma F.D., D'Alessandro A., Esposito G. Impaired DuodenalPalmitoylethanolamide Release Underlies Acid-Induced Mast Cell Activation inFunctional Dyspepsia. Cell Mol Gastroenterol Hepatol. 2020 Oct 14. PMID:33065341

13.    Duan Z, Lu J.*DNA Methyltransferases inDepression: An Update. Front Psychiatry. 2020 Sep 3,PMID: 33101076  IF=2.849

14.    Pesce M., Seguella L.,Cassarano S., Aurino L., Sanseverino W., Lu J., Corpetti C., Del Re A.,Vincenzi M., Sarnelli G., Esposito G. Phytotherapics in COVID19: Why palmitoylethanolamide?Phytother Res. 2020 Dec 9. doi: 10.1002/ptr.6978. PMID: 33296131

15.    Qin L., Qiao C., Sheen V., Wang Y.*,Lu J. *DNMT3Lpromotes neural differentiation by enhancing STAT1 and STAT3 phosphorylationindependent of DNA methylation. Prog Neurobiol. 2021 Feb 23, PMID: 33636226  IF=11.68

16.    Adnan A,Rakha A, Nazir S, Alghafri R, Hassan Q, Wang CC, Lu J.* Forensicfeatures and genetic legacy of the Baloch population of Pakistan and the Hazarapopulation across Durand line revealed by Y-chromosomal STRs. Int J LegalMed. 2021 Sep;135(5):1777-1784. PMID: 33818632. JCR 1, IF=2.686.

17.    Esposito G,Pesce M, Seguella L, Lu J, Corpetti C, Del Re A, De Palma FDE, EspositoG, Sanseverino W, Sarnelli G. Engineered Lactobacillus paracasei ProducingPalmitoylethanolamide (PEA) Prevents Colitis in Mice. Int J Mol Sci. 2021Mar 14;22(6):2945. PMID: 33799405

18.    Esposito G,Corpetti C, Pesce M, Seguella L, Annunziata G, Del Re A, Vincenzi M, LattanziR, Lu J, Sanseverino W, Sarnelli G. A Palmitoylethanolamide ProducingLactobacillus paracasei Improves Clostridium difficile Toxin A-Induced Colitis.Front Pharmacol. 2021 Apr 27;12:639728. PMID: 33986673

19.    Pesce M,Seguella L, Del Re A, Lu J, Palenca I, Corpetti C, Rurgo S, SanseverinoW, Sarnelli G, Esposito G. Next-Generation Probiotics for Inflammatory BowelDisease. Int J Mol Sci. 2022 May 13;23(10):5466. PMID: 35628274.

20.    Zhang Z,Zhang X, Wu X, Zhang Y, Lu J*, Li D*. Sirt1 Attenuates AstrocyteActivation Via Modulating Dnajb1 and Chaperone-Mediated Autophagy After ClosedHead Injury. Cereb Cortex. 2022 Feb 1;bhac007. PMID: 35106540. IF=5.38

21.    Han K, KangN, Yu X, Lu J*, Ma Y*. lncRNA NEAT1-let 7b-P21 axis mediates theproliferation of neural stem cells cultured in vitro promoted by radialextracorporeal shock wave. Regen Ther. 2022 Jul 1;21: 139-147. doi:10.1016/j.reth.2022.06.006. eCollection 2022 Dec. PMID: 35844294, JCR 3, IF=2.35

22.    Sarnelli G,Del Re A, Pesce M, Lu J, Esposito G, Sanseverino W, Corpetti C, BasiliFranzin S, Seguella L, Palenca I, Rurgo S, De Palma FDE, Zilli A, Esposito G. OralImmunization with Escherichia coli Nissle 1917 Expressing SARS-CoV-2 Spike ProteinInduces Mucosal and Systemic Antibody Responses in Mice. Biomolecules2023， 13(3):569. doi: 10.3390/biom13030569 PMID: 36979504.

23.    Shaikh A, LiYQ*, Lu J*, Perspectives on pain in Down syndrome. Medicinal ResearchReviews 2023 Mar 16. https://doi.org/10.1002/med.21954  PMID: 36924439, JCR 1, IF=12.39

24.    Guo S, Yu T,Chen X, Cui M, Liu D, Xu S, Lu J, Zhang H. Variations of the doublesuperior mesenteric vein are not rare: An observational study using computedtomography, three-dimensional image reconstruction, and surgery. Eur J Surg Oncol. 2023 Jul 9:106972. doi:10.1016/j.ejso.2023.06.024. PMID: 37455181