Exploring a novel molecular pathway that underlies cerebellar contribution to autism spectrum disorder
| Project/Area Number |
23K14826
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52030:Psychiatry-related
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| Research Institution | Tokai University |
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Principal Investigator |
モハメド ダルウィシュ 東海大学, 医学部, 奨励研究員 (60938934)
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| Project Period (FY) |
2023-04-01 – 2025-03-31
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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2024: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2023: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | Neurotropic factors / cerebellum development / ASD / Cerebellum |
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| Outline of Research at the Start |
The cerebellum has been involved in neurodevelopmental disorders such as autism spectrum disorders (ASD). However, the molecular mechanism underlying cerebellar development/function and its implication in ASD are not fully understood. We identified a novel neurotropic factor as a potential key molecule for cerebellar development and ASD. I will use mouse genetics, together with molecular, electrophysiological, and behavioral approaches to uncover a novel molecular pathway that underlies cerebellar development and its involvement in ASD pathophysiology.
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| Outline of Annual Research Achievements |
In the first fiscal year, I aimed to elucidate the receptor and signaling pathway of NDNF that work together to maintain proper brain development. To identify NDNF receptors and other binding partners, I performed co-immunoprecipitation-coupled mass spectrometry from HA-tagged NDNF mice brain and identified potential receptor and downstream signaling pathway for NDNF. Indeed, I confirmed this pathway using westernblot analysis. In addition, we discovered that the NDNF undergoes processing and cleavge into a potentially more potent form. Using in vitro experiments, this cleaved form showed superior effect compared to full-length NDNF.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
I think that the progress during the first year was going well becasue we identified a novel signaling patwhay through NDNF that underlie brain development and function. In addition, we identified a potential active form of NDNF which could have a great therapeutic potential for treating neurodevelopmental disorders.
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| Strategy for Future Research Activity |
In the next year, I plan to investigate whether NDNF receptor is involved in cerebellum development and the pathophysiology of neurodevelopmental disorders, I will knockout the receptor in the cerebellum using virus-based in vivo genome editing and compare morphological and behavioral characteristics to those of Ndnf KO mice. Next, I will investigate whether activating NDNF signaling pathway restores cerebellum function in Ndnf KO mice to confirm causality between NDNF signaling pathways and brain development.
Besides, I aim to check the theraputic potential of NDNF in treating neurodevelopmental disorders. I will inject the cleaved and full length peptide into the cerebellum of neonatal Ndnf KO mice to investigate its therapeutic effect in preventing neurodevelopmental phenotypes.
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Report
(1 results)
Research Products
(2 results)
