Pharmacological study of a shared genetic risk factor for osteoporosis and Alzheimer's disease
| Project/Area Number |
23K09116
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 57010:Oral biological science-related
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| Research Institution | Hokkaido University |
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Principal Investigator |
李 智媛 北海道大学, 歯学研究院, 助教 (70711274)
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| Co-Investigator(Kenkyū-buntansha) |
飯村 忠浩 北海道大学, 歯学研究院, 教授 (20282775)
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| Project Period (FY) |
2023-04-01 – 2026-03-31
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| Project Status |
Granted (Fiscal Year 2023)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2025: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2024: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | Pyk2 / osteoclasts / microglia / ontogeny / osteoporosis / Alzheimer's disease / osteoclast / PTK2B |
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| Outline of Research at the Start |
To find functional roles of Pyk2 that are associated between osteoporosis and AD, we will 1) elucidate physiological mechanism of Pyk2 in osteoclast and microglia, and 2) dissociate role of Pyk2 inhibition in pathophysiology of osteoporosis and AD using mouse disease model.
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| Outline of Annual Research Achievements |
Our first-year plan is as follows: Elucidating the molecular mechanism of Pyk2 on the ontogeny of osteoclasts and microglia in vitro, using Pyk2 inhibitor. Following the plan, we conducted molecular biology investigations into the effects of utilizing a target inhibitor of Pyk2, a convergence gene we discovered, on osteoclasts and microglia. We demonstrated that inhibiting Pyk2 in microglia enhances phagolysosomal activities against Aβ oligomers both in vitro. In vivo, the administration of the Pyk2 inhibitor led to an increased migration of microglia toward deposits in the brains of Iba-1 EGFP transgenic mice, accompanied by morphological activation, suggesting a heightened affinity for Aβ. Furthermore, we confirmed that Pyk2 inhibitor inhibited the osteoclast differentiation. In vitro, Pyk2 inhibition significantly impedes osteoclast differentiation and bone resorption. In a co-culture system comprising osteoblasts and osteoclasts, Pyk2 inhibitor effectively suppressed osteoclast differentiation, accompanied by a substantial increase in the transcriptional expression of Tnfrsf11b and Csf1 in osteoblasts.
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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
My research is progressing as planed in proposal.
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| Strategy for Future Research Activity |
By employing a 3rd generation double tg (App/Psen1) mouse model for AD, and harnessing cutting-edge analytical tools like FTIR imaging and spatial transcriptomics, we aim to evaluate the impact of Pyk2 inhibition on Aβ deposition.
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Report
(1 results)
Research Products
(5 results)
