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High-probability grants
According to our matching algorithm, Anthony J. Filiano is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2008 |
Filiano, Anthony J |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Transglutaminase 2 Decreases Ischemic Insult by Attenuating Hypoxic Signaling. @ University of Rochester
[unreadable] DESCRIPTION (provided by applicant): Stroke is the third leading cause of death and a major cause of long term disability in the US. Inadequate success of current thrombolytic therapy demonstrates a critical need for new targets to improve quality of life post-stroke. Neurons adapt to decreased oxygen delivery subsequent to stroke by up-regulating genes controlled by the hypoxia inducible factor (HIF). This transcription factor is comprised of two subunits: HIF1 alpha and HIF1 beta. Recent studies show that increased HIF1 during ischemia results in upregulation of apoptotic genes. Our preliminary data indicates that Transglutaminase 2 (TG2) binds to HIF1 beta resulting in attenuation of HIF activation and decreased cell death during ischemia. Also, TG2 inhibits the upregulation of the HIF controlled proapoptotic gene Bnip3, but not VEGF. Our hypothesis is that TG2 will facilitate neuronal protection following oxygen and glucose deprivation (OGD) by attenuating apoptotic genes induced by HIF1. We propose to delineate the effects of TG2 on HIF signaling and ischemic cell death with 3 aims. 1) To test the hypothesis that TG2 is upregulated during OGD and decreases HIF-dependent pro-apoptotic signaling. We will use a neuroblastoma cell line (SH-SY5Y) that overexpresses wild type TG2 and two TG2 constructs with point mutations that differentially affect 2 unique functions (transamidating and GTPase) of the enzyme. Using a HIF signaling reporter assay and analysis of mRNA and protein expression patterns of HIF dependent genes, we will distinguish which properties of TG2 are important for regulating HIF signaling. 2) To test the hypothesis that TG2 protects neuronal cells from ischemic insult and which functions of TG2 are important. Using SH-SY5Y cells and primary cortical neurons we will measure OGD-induced cell death and upstream apoptotic events. 3) To test the hypothesis that TG2 leads to overall protection in a mouse model of stroke. We will use a permanent Middle Cerebral Artery ligation model in C57BL/6 mice that express endogenous TG2, overexpress TG2, or lack TG2. We will measure infarct volumes using T2 weighted MRI as well as identifying genes regulated by TG2 with appropriate techniques. Our preliminary data show that overexpression of TG2 decreases stroke infarct volumes by 33%. We hypothesize that TG2 will lead to overall protection against stroke. [unreadable] [unreadable]
|
0.961 |
2021 |
Filiano, Anthony J |
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. |
Pericyte-Macrophage Interactions Maintain Cns Immune Tolerance
Pericyte-Macrophage Interactions Maintain CNS Immune Tolerance ABSTRACT Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) where infiltrating T cells ultimately lead to the destruction of myelin. T cells initially accumulate in the perivascular space of the brain and the meninges where they must interact with antigen presenting cells prior to activating and infiltrating into the parenchyma. This suggests immune interactions in the perivascular space may serve as a checkpoint and determine the fate of infiltrating T cells. Macrophages and pericytes are two important cells in the perivascular space of the brain and meninges. Under homeostatic conditions, border macrophages have an immuno- surveillant phenotype and express surface markers typical for macrophages that help with healing tissues. The signals that maintain CNS border macrophages in this state are unknown. Pericytes also reside in the perivascular space and are a key component of the neurovascular unit where they regulate blood flow, angiogenesis, the blood-brain barrier (BBB), and neuroinflammation. Although each cell type has be implicated in multiple sclerosis (MS), the communication between the 2 cell types has not been described. Our preliminary data demonstrate that cultured pericytes suppress the activation of T cells through engaging macrophages. Pericytes directly contact macrophages and reprogram them to downregulate genes need for antigen presentation and T cells activation. Pericytes/macrophage interactions are mediated by lipoprotein receptor- related proteins (LRP) on macrophages and dependent on p-bodies in pericytes. P-bodies are membrane-less, cytoplasmic organelles that contain mRNAs enriched in regulatory functions. In vivo, pericytes reside in close proximity to perivascular and meningeal macrophages and have the potential to interact closely with macrophages. When we deleted pericytes in vivo, CNS antigen specific T cells infiltrate the perivascular space of the meninges in a manner that was dependent on macrophages. T cells further infiltrate into the parenchyma when triggered by a second signal from the parenchymal. We hypothesize that under homeostatic conditions pericytes communicate with perivascular and meningeal macrophages to maintain them in an immunosuppressive and surveillant state. This contributes to the immuno- privileged nature of the brain. In MS, we hypothesize that communication between pericytes and macrophages breakdown and this unleashes CNS macrophages into a proinflammatory state that contributes to T cell activation and infiltration into the brain. In this proposal, we will determine if pericytes instruct perivascular macrophages to inhibit brain-specific T cells from entering the parenchyma, investigate whether pericytes reprogram CNS macrophages in vivo, and determine if macrophages must engulf components of pericytes in order to be reprogramed to suppress T cells. Overall, this proposal will investigate an unexplored interaction between pericytes and CNS border macrophages.
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0.97 |