| Project/Area Number |
20K07458
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 49030:Experimental pathology-related
|
|---|
| Research Institution | Okinawa Institute of Science and Technology Graduate University |
|---|
Principal Investigator |
Terenzio Marco 沖縄科学技術大学院大学, 分子神経科学ユニット, 准教授 (60867513)
|
|---|
| Project Period (FY) |
2020-04-01 – 2024-03-31
|
| Project Status |
Completed (Fiscal Year 2023)
|
| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
|
|---|
| Keywords | ALS / motor neurons / LPS / biomarkers / hIPSC / IPSC / RNA sequencing / axonal translation / disease onset / protein translation / human IPSC / MNs |
|---|
| Outline of Research at the Start |
To overcome the limitations of murine models, we plan to directly derive motor neurons (MNs) from Amyotrophic Lateral Sclerosis (ALS) patient’s fibroblasts to assess changes in axonal local translation. Axonal degeneration is a primary pathological event determining the demise of MNs in ALS and defects of axonal translation contribute to the axonal pathology. We will investigate differences in axonal translation and test any abnormal protein expression as a possible new biomarker of disease and/or target of new therapies in biological fluids from well characterized cohorts of ALS patients.
|
| Outline of Final Research Achievements |
Our research aimed to understand ALS progression by deriving motor neurons (MNs) from ALS patient human pluripotent steam cells (hIPSCs), overcoming murine model limitations. Key achievements include:
1. Developing microfluidic chambers for axonal biology studies of MNs derived from ALS patients hIPSCs. 2. Enhancing MN differentiation yield from hIPSCs to over 70%. 3. Recapitulating ALS pathology, observing axonal degeneration, mitochondrial dysfunction, and protein aggregation in ALS MN cultures. 4. Identifying a mechanisms linking decrease in intracellular ATP levels to an increase of toxic TDP43 aggregation in ALS MNs. 5. Identifying potential ALS biomarkers from culture medium, with ongoing validation.
|
| Academic Significance and Societal Importance of the Research Achievements |
ALS rapidly leads to death. Our research links mitochondrial defects and reduction of ATP, to cytoplasmic aggregates in motor neurons from ALS patients, expanding on the role of LPS in disease. We also identified possible biomarkers for diagnosis, to improve patients` treatment and quality of life.
|
