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High-probability grants
According to our matching algorithm, Xiaoming Hu is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2015 — 2020 |
Hu, Xiaoming |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Immunomodulation of White Matter Integrity After Stroke @ University of Pittsburgh At Pittsburgh
? DESCRIPTION (provided by applicant): White matter (WM) injury, characterized by demyelination and loss of axonal integrity, is an important cause of long-term sensorimotor and cognitive deficits after stroke. A persistent pro-inflammatory microenvironment after stroke is considered one underlying mechanism that hinders oligodendrocyte precursor cell (OPCs) differentiation and maturation into myelinating oligodendrocytes (OLs). Accumulating recent evidence suggests that the different functional phenotypes of microglia/macrophages contribute considerably to the regulation of inflammatory status of injured WM and ultimately impact the WM integrity. Specifically, alternatively activated M2 microglia are essential for remyelination and WM repair because they resolve local inflammation, clear broken myelin sheath or cellular debris, and provide trophic factors that promote OPC differentiation. Interleukin-4 (IL-4) is thus far the best characterized inducer for M2 polarization of microglia/macrophages; however, its role in microglia regulation in WM and long term stroke outcomes is not known. We have discovered that IL-4 is a novel endogenous protectant against WM injury and that it promotes WM repair. Our preliminary results show that IL-4 knockout (KO) mice exhibit worse sensorimotor deficits over 14 days after tMCAO. Remarkably, IL-4 KO mice display deteriorated WM injury. Moreover, IL-4 KO mice show markedly reduced numbers of M2 microglia/macrophages in WM-enriched brain regions, including the corpus callosum and striatum after tMCAO. In contrast, intraventricular infusion of IL-4 for 14 days beginning 6h after MCAO attenuates long-term sensorimotor and cognitive deficits and improves WM integrity. In addition to promoting M2 polarization, we have found that IL-4 directly induces the differentiation of primary OPCs into mature OLs at nanomolar concentrations and that this effect of IL-4 on OPCs is mediated through the activation of PPAR?. In this proposal, we will focus on the novel action of IL-4 on WM integrity and explore the underlying mechanisms. We will test the overarching hypothesis that IL-4 promotes WM integrity and long-term neurological recovery after stroke by dual mechanisms, in that it 1) promotes OPC differentiation/maturation via PPAR? activation and 2) potentiates microglia/macrophage polarization toward the beneficial M2 phenotype, which is essential for remyelination and WM repair in demyelinating brains. The Specific Aims to be tested are: Aim 1: Test the hypothesis that post-ischemia IL-4 treatment enhances WM integrity and long-term neurological recovery after stroke. IL-4 will be delivered into the brain by repeated intranasal administrations after reperfusion. The endpoints for assessment include neurological outcomes and various markers for WM integrity. Aim 2: Test the hypothesis that IL-4 induces OPC differentiation into mature OLs and promotes axonal remyelination via PPAR? activation. Aim 3: Test the hypothesis that IL-4 potentiates microglia/macrophage polarization into the inflammation-resolving, tissue repair-enhancing M2 phenotype and restores a healthy microenvironment for efficient WM repair.
|
0.948 |
2016 — 2020 |
Hu, Xiaoming |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulatory T Cell as a Restorative Therapy For Ischemic Stroke @ University of Pittsburgh At Pittsburgh
? DESCRIPTION (provided by applicant): White matter (WM) lesions, characterized by the loss of myelin and myelin-producing oligodendrocytes (OLs), are a major cause of functional disability after stroke but have not been widely appreciated in therapeutic studies until recently. Here we propose to rectify this gap in the field by focusing on WM integrity and its modulation by immune responses in the ischemic brain. Activated microglia/macrophages of distinct phenotypes are known to determine OL cell fate and WM integrity after brain injuries. Specifically, the alternatively activated M2 phenotype is essential for WM preservation and repair because M2 cells resolve local inflammation, clear broken myelin sheaths, and provide trophic factors that promote WM repair. CD4+CD25+ regulatory T cells (Tregs) are a specialized subpopulation of T cells that negatively regulate immune responses. Our recent study demonstrated that adoptive Treg therapy exerted early neuroprotection by targeting inflammatory dysregulation and neurovascular disruption after stroke. However, it is not known whether Tregs also have a beneficial effect on WM integrity. Recently, we discovered that Treg-conditioned media stimulates microglial polarization toward the M2 phenotype, and M2 microglia enhance OL survival and promote OPC differentiation in vitro. These exciting results suggest that Tregs can preserve WM integrity. We obtained further promising data showing that 1) Treg transfer at 2h of reperfusion reduced the extent of WM injury and improved sensorimotor functions for at least 28d after transient middle cerebral artery occlusion (tMCAO); 2) Post-stroke Treg treatment resulted in a long-lasting elevation of IL-10, a major Treg-derived cytokine that is important for WM repair; 3) Treg treatment promoted M2 polarization of microglia/macrophages in both WM and gray matter after tMCAO. Furthermore, we have successfully induced a robust increase of Tregs in the circulation after stroke by systemic injection of interleukin (IL)-2/IL-2 antibody complex (IL-2/IL- 2Ab), an established approach to expand Tregs in vivo. We demonstrated that IL-2/IL-2Ab-induced Treg expansion reduces myelin loss 7d after tMCAO and improves sensorimotor functions. The current proposal will further explore the effects of Tregs on WM injury and repair after stroke and develop in vivo Treg expansion as a novel strategy to promote WM integrity and enhance post-stroke recovery. The central hypothesis to be tested is that Tregs promote WM integrity and long-term recovery after stroke by polarizing microglia/macrophages toward the M2 phenotype in an IL-10 dependent manner. Three specific aims are proposed: Aim 1. Test the hypothesis that Treg treatment after stroke improves long-term functional recovery and promotes WM integrity. Aim 2. Test the hypothesis that Treg-derived IL-10 shifts microglia/macrophage polarization towards the M2 phenotype, thereby promoting WM integrity after stroke. Aim 3. Test the hypothesis that in vivo expansion of Tregs with post-stroke IL-2/IL-2Ab treatment is effective in reducing long-term WM injury and improving neurological recovery after stroke.
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0.948 |