Investigating the role of TDP-43 mislocalization, structure, and post-translational modifications in the neuropathologically heterogeneous TDP-43 proteinopathies
Active Project Grant Awarded Last action
- Award ID
- R01NS137469
- Recipient
-
Trustees Of Indiana University UEI SHHBRBAPSM35
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $4,859,076
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date 51% complete
- Funding agency
- National Institute on Aging National Institutes of Health, Department of Health and Human Services
- Place of performance
- Indianapolis, IN 46202, USA
Award details come from USAspending.gov.
Description
- Abstract
- The abnormal aggregation of transactive response DNA-binding protein of 43 KDA (TDP-43) in neuronal inclusions is the defining pathologic hallmark of approximately half of frontotemporal lobar degeneration cases (FTLD-TDP). Substantial heterogeneity exists in the clinical disorders associated with FTLD-TDP, which reflects regional differences in neurodegeneration. Neuropathologic studies have suggested that the regional cortical burden of aggregated TDP-43 may be responsible for neurodegeneration and ensuing clinical heterogeneity. However, the molecular mechanisms underlying the region-specific accumulation of aggregated TDP-43 are not understood. We hypothesize that: 1) in view of the subdivision of FTLD-TDP types (a-D) and variability in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), presence of atypical neuropathologic features may signal novel TDP-43 structures and post-translational modifications (PTMS); 2) among TDP-43 proteinopathies, each neuropathologic phenotype is related to a distinct structure of TDP-43 filaments, TDP-43 PTMS, and seeding properties. To investigate these hypotheses, we propose to combine our collective expertise in neuropathology, molecular genetics, molecular characterization of misfolded proteins, fluorescent multiplex immunohistochemistry, digital spatial profiling, quantitative digital image analysis, and cryo-electron microscopy to study our study population, which includes clinicopathologically well-characterized cases from the dementia laboratory's brain library and cases from other researchers. The project specific aims provide a foundation for in-depth analysis of TDP-43 proteinopathies. Aim 1 combines innovative neuropathologic methods for mapping TDP-43 inclusions, misfolded TDP-43 in different neuronal and glial populations, glial response, and for determining how TDP-43 amyloid folds relate to the phenotype. Aim 2 leverages cutting-edge technology to identify novel PTMS that coexist with the presence of misfolded TDP-43. RT-quic assay might reveal differences of TDP-43 seeding properties. Aim 3 uses the most advanced cryo-EM technology to determine the structures of the TDP-43 amyloid filaments.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $120,341 | |
| Amendment | $849,495 | |
| Amendment | $849,495 | |
| Amendment | $980,431 | |
| Amendment | $1,029,657 | |
| Original award | $1,029,657 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Universita Degli Studi DI Verona | $37,976 | |
| UK Research & Innovation | $301,653 |
Quick answers
Who received award R01NS137469?
R01NS137469 was awarded to Trustees Of Indiana University by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on April 16, 2024.
How much is award R01NS137469 worth?
$4,859,076 has been obligated on R01NS137469.
Which agency awarded R01NS137469?
National Institute of Neurological Disorders and Stroke (National Institutes of Health) awarded R01NS137469, with funding from National Institute on Aging (National Institutes of Health).
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