Novel molecular strategies to promote functional recovery after traumatic brain injury

Traumatic brain injury (TBI) and post-TBI neurological sequelae are a major medical concern for US military
veterans. There is no effective therapy to battle the catastrophic neurological disabilities after TBI, in part
because most neuroprotective therapies against TBI target gray matter but neglect the importance of white
matter (WM) injury, the degree of which dictates the severity of long-term neurological deficits. A persistent
proinflammatory microenvironment after TBI is considered one underlying mechanism that exacerbates WM
injury and hinders WM repair. Microglia and macrophages (Mi/MΦ) are important mediators of post-TBI immune
and inflammatory responses and can assume diverse functional states in response to specific
microenvironmental signals. Accumulating evidence suggests that the different functional phenotypes of Mi/MΦ
contribute considerably to the regulation of inflammatory status of injured WM and ultimately impact WM integrity.
Specifically, an inflammation-resolving and protective/reparative phenotype of Mi/MΦ is essential for mitigating
WM injury and facilitating WM repair because they resolve local inflammation, clear broken myelin sheath or
cellular debris, and supply trophic factors for brain remodeling. The key molecular switches and networks that
determine the overall functional state of Mi/MΦ after TBI are poorly understood.
To fill this critical scientific gap, we propose to investigate salt-inducible kinases (SIKs) as novel regulators
of Mi/MΦ functions after experimental TBI. SIKs potently control gene expression by directly acting on several
specific transcriptional regulators. Thus, SIK activation lies at the apex of a decision tree for arbitrating between
polymorphic, often-opposing immune responses in Mi/MΦ. The scientific premise underlying the engagement of
SIK as a candidate biological target for TBI is its ability to titrate immune balance toward inflammation-resolving
and protective/reparative phenotypes, while avoiding indiscriminate suppression of immune function.
The scientific premise of this proposal is also strengthened by our new preliminary discoveries: 1) TBI
elevates SIK1 expression and activity (phosphorylation) in Mi/MΦ but not in other brain cells in mice; 2)
Tamoxifen-induced selective knockout of SIK1 in Mi/MΦ (mKO) improves long-term sensorimotor functions and
spatial memory after TBI, confirming a crucial role of Mi/MΦ SIK1 in TBI neurological outcomes; 3)
Mechanistically, SIK1 mKO drives Mi/MΦ toward an inflammation-resolving and protective/reparative phenotype
after TBI, thus restricting axonal injury and promoting WM repair; 4) Intraperitoneal delivery of YKL-05-099 (YKL),
a novel selective SIK inhibitor, attenuates neuroinflammation and neurological deficits after TBI. Accordingly, the
proposed studies will test the core hypothesis that genetic deletion or pharmacological inhibition of SIK1
improves white matter restoration and long-term TBI outcomes by dual mechanisms: 1) protecting
against early axonal injury by promoting inflammation-resolving Mi/MΦ responses; and 2) enhancing
chronic-stage white matter restoration by promoting a reparative Mi/MΦ phenotype.
If funded, we will tackle three Specific Aims in a timely and efficient manner. Aim 1: Test if administration
of a selective SIK inhibitor improves long-term TBI outcomes for up to 20 weeks. We will assess the therapeutic
effects of the SIK inhibitor YKL, delivered i.p. after controlled cortical impact (CCI) to adult C57BL/6 mice of both
sexes. Aim 2: Test if YKL attenuates axonal injury at acute/subacute stages via inhibition of SIK1-dependent
neurotoxic Mi/MΦ responses. This mechanistic aim will study the role of Mi/MΦ SIK1 using tamoxifen-induced
Mi/MΦ-specific SIK1 knockout (SIK1 mKO) and wild-type control mice of both sexes. Aim 3: Test if YKL or SIK1
mKO promotes WM restoration and long-term recovery after TBI for up to 20 weeks by fostering a neurotrophic/
pro-repair Mi/MΦ phenotype.
A rigorously confirmed beneficial effect of YKL would facilitate its clinical translation into a novel potential
therapeutic for TBI to enhance brain rehabilitation and improve the quality of life for veterans suffering TBI.

Grant Number: 5I01BX003377-08
NIH Institute/Center: VA
Principal Investigator: Jun Chen