Aviva Symes, Ph.D.

Aviva J Symes, Ph.D.

Name: Aviva J Symes, Ph.D.

USU Department of Primary Appointment: 
Pharmacology & Molecular Therapeutics
Faculty Rank: 
Full Professor
Location: 
Uniformed Services University of the Health Sciences, Bethesda, MD

Research Interests:
Traumatic brain injury
Role of renin angiotensin system in the brain after injury

Office Phone: 
(301) 295-3234

Education

B.Sc.(Hons). Biochemistry, University of Manchester, UK
Ph.D. Biochemistry/Molecular Biology, University College London, UK
Post-doctoral training: Massachusetts General Hospital/ Harvard Medical School, Boston.

Biography

RESEARCH INTERESTS:

My lab aims to understand the mechanisms through which the brain responds to traumatic injury and more specifically to delineate the pathways through which detrimental neuroinflammatory cascades can be altered to enhance recovery after injury. The initial lesion can produce significant tissue damage and breakdown of the blood brain barrier. These immediate effects lead to activation of many secondary cascades involving interplay between endogenous surviving neurons and glia, and infiltrating cells and molecules from the bloodstream. Injury therefore leads to acute neuroinflammatory cascades, and also to more chronic inflammatory effects. Indeed, activated microglia have been documented in postmortem brains many years after the initial insult. Our lab focuses on understanding the molecular signaling cascades that occur after injury in addition to testing potential therapeutics to enhance recovery from injury. We currently utilize several different rodent models of traumatic brain injury (TBI), with assays ranging from behavioral through molecular to understand the complex interactions that occur after injury, and to determine how manipulations may impact on functional recovery. We also utilize primary cell cultures to tease apart the molecular signaling pathways that contribute to inflammation after injury.

Angiotensin receptor blockers as potential therapeutics for TBI
Angiotensin receptor blockers (ARBs) are widely used FDA-approved anti-hypertension drugs with a favorable side effect profile that have been used as a mechanism for reducing the amount of TGF-β signaling in several different organ systems. In the CNS, ARBs have also been shown to be neuroprotective, anti-inflammatory and protective of the cerebral blood flow (CBF). The brain possesses its own renin angiotensin system, with many different components of the system expressed in the different cell types in the brain. However, in addition to acting as antagonists at the Angiotensin II receptor 1 (AT1R) some ARBs also possess potent PPARγ agonist activity that enhances their anti-inflammatory action. We have demonstrated that the ARB candesartan, lessens inflammation, reduces lesion volume, limits glial reactivity, increases neuronal survival and improves motor and cognitive recovery up to 28 days after injury. These beneficial effects are seen when low-dose candesartan is administered up to 6 hours after injury, a clinically acceptable therapeutic window. Our data suggest that both AT1 receptor antagonism and PPARγ agonism contribute to the efficacy of ARB treatment after TBI and it is this multimodal action by a single drug that makes it a strong candidate for TBI clinical trials. We are pursuing translational studies for candesartan for brain injury in addition to investigating the consequences of TBI on the endogenous renin-angiotensin system in the brain.

TGF-β signaling after injury
TGF-β is an injury induced cytokine that has complex roles in the central nervous system. After brain injury TGF-β can promote astrogliosis and enhance the deposition of molecules inhibitory to regeneration in the glial scar. Yet TGF-β is also neuroprotective indicating the sometimes conflicting roles of this cytokine. We have shown that after a penetrating brain injury mice that lack expression of the TGF-β signaling molecule Smad3, form a glial scar more quickly, with a smaller scar, than wild type mice. However, we also found that Smad3 null mice have more pronounced neuronal loss after injury. Thus, global interference with TGF-β signaling is not a desirable therapeutic option. Further, TGF-β is anti-inflammatory in some contexts – so chronic repression of TGF-β signaling pathways may enhance inflammation. In primary microglial cultures we have shown that inflammatory pathways downregulate TGF-β receptor expression, allowing for prolonged enhancement of the inflammatory activated state.

Bibliography

  • Bone morphogenetic protein-2-mediated pain and inflammation in a rat model of posterolateral arthrodesis. Mitchell K, Shah JP, Dalgard CL, Tsytsikova LV, Tipton AC, Dmitriev AE, Symes AJ. BMC neuroscience. 2016; 17(1):80. PubMed [journal]PMID: 27905881 PMCID: PMC5134101
  • Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Villapol S, Balarezo MG, Affram K, Saavedra JM, Symes AJ. Brain : a journal of neurology. 2015; 138(Pt 11):3299-315. PubMed [journal]PMID: 26115674 PMCID: PMC4731413
  • Runx1 promotes proliferation and neuronal differentiation in adult mouse neurosphere cultures. Logan TT, Rusnak M, Symes AJ. Stem cell research. 2015; 15(3):554-564. PubMed [journal]PMID: 26473321
  • Hepatic expression of serum amyloid A1 is induced by traumatic brain injury and modulated by telmisartan. Villapol S, Kryndushkin D, Balarezo MG, Campbell AM, Saavedra JM, Shewmaker FP, Symes AJ. The American journal of pathology. 2015; 185(10):2641-52. PubMed [journal]PMID: 26435412 PMCID: PMC4607758
  • . Temporal patterns of cortical proliferation of glial cell populations after traumatic brain injury in mice. Susarla BT, Villapol S, Yi JH, Geller HM, Symes AJ. ASN neuro. 2014; 6(3):159-70. PubMed [journal]PMID: 24670035 PMCID: PMC4013687
  • LPS antagonism of TGF-β signaling results in prolonged survival and activation of rat primary microglia. Mitchell K, Shah JP, Tsytsikova LV, Campbell AM, Affram K, Symes AJ. Journal of neurochemistry. 2014; 129(1):155-68. PubMed [journal]PMID: 24251648
  • Temporal dynamics of cerebral blood flow, cortical damage, apoptosis, astrocyte-vasculature interaction and astrogliosis in the pericontusional region after traumatic brain injury. Villapol S, Byrnes KR, Symes AJ. Frontiers in neurology. 2014; 5:82. PubMed [journal]PMID: 24926283 PMCID: PMC4044679
  • Smad3 deficiency increases cortical and hippocampal neuronal loss following traumatic brain injury. Villapol S, Wang Y, Adams M, Symes AJ. Experimental neurology. 2013; 250:353-65. PubMed [journal]PMID: 24120438
  • TGF-β superfamily gene expression and induction of the Runx1 transcription factor in adult neurogenic regions after brain injury. Logan TT, Villapol S, Symes AJ. PloS one. 2013; 8(3):e59250. PubMed [journal]PMID: 23555640 PMCID: PMC3605457
  • Candesartan, an angiotensin II AT₁-receptor blocker and PPAR-γ agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice. Villapol S, Yaszemski AK, Logan TT, Sánchez-Lemus E, Saavedra JM, Symes AJ. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2012; 37(13):2817-29. PubMed [journal]PMID: 22892395 PMCID: PMC3499714