FAM76B as a critical regulator of neuroinflammation in frontotemporal lobar degeneration

Project: Research project

Project Details

Description

Specific aim(s)/objective(s): To elucidate FAM76B’s biological function in regulating inflammation and neuroinflammation.

Background: Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia in patients younger than 65 years of age and is characterized by progressive changes in behavior, personality, and language (1). One of the most common genetic causes of FTLD is the heterozygous loss-of-function mutation in the progranulin gene, GRN, which encodes for a glycosylated protein, PGRN (2, 3). Neuroinflammation plays a central role in the pathogenesis of GRN mutation-associated FTLD. Studies have shown that PGRN deficiency leads to the dysfunction of microglial cells, the key mediators of neuroinflammation (4, 5). However, the mechanism by which PGRN deficiency leads to microglial dysfunction is still unknown.

Design including subject population(s) and hypothesis: Our hypothesis is that FAM76B exerts its anitinflammatory function through blockade of NF-κB–IL-6 signaling. This is proposed based on our preliminary data that FAM76B, a nuclear localized protein of previously unknown function, binds to PGRN to suppress the inflammation mediated by macrophages. Overexpression or knockdown of FAM76B downregulated or upregulated the expression of pro-inflammatory cytokines, especially IL-6. To test this hypothesis, we aim to determine whether FAM76B affects the activity of the IL-6 promoter and whether the expression of FAM76B in the human brain is influenced by the GRN mutation. The proposed study will elucidate, for the first time, FAM76B’s biological function in partnering with PGRN to regulate inflammation and neuroinflammation. This pilot study will provide the basis for future projects to explore how aberrant PGRN–FAM76B interactions contribute to microglial dysfunction and the pathogenesis of FTLD, and uncover novel therapeutic targets for FTLD.
StatusFinished
Effective start/end date6/1/186/30/19

Funding

  • Illinois Department of Public Health (93282003G)

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