Mirzadeh Laboratory
About
As part of the Ivy Brain Tumor Center, the Mirzadeh Lab is using our understanding of metabolism to identify unique metabolic pathways co-opted by glioblastoma to drive tumor growth. Emerging evidence that these metabolic processes within glioblastoma may be ideal therapeutic targets will allow for combinatorial approaches, together with more traditional targets in cell cycle regulation, to prevent the development of tumor resistance and progression.
current Research
The related metabolic disorders of type 2 diabetes (T2D) and obesity have reached epidemic proportions in both children and adults in the United States and therapeutic advances have not kept pace to curtail the growing healthcare burden. New therapeutic approaches are critically needed that address the causes rather than the manifestations of these diseases. Accumulating evidence implicates the brain’s hypothalamic circuits in the homeostatic defense of blood glucose and body fat mass, and suggests that defects in these circuits may result in defense of an elevated blood glucose level in T2D and an elevated fat mass level in obesity. Stated differently, the fundamental hypothesis that emerges is that the brain establishes normal set points for blood sugar and body fat mass, and due to a defect in this central control, the set points become abnormally elevated in T2D and obesity, respectively. To develop more effective and sustained therapies for diabetes, obesity, and related metabolic disorders, our goal is to understand how the brain normally establishes the set points for glucose and energy homeostasis, how this control goes awry in disease states like diabetes and obesity, and how neurocircuit remodeling may be employed to re-establish normal metabolic set points.
Show More
Recent work shows that in rodent models, T2D remission lasting months can be induced by a single intracerebroventricular injection of fibroblast growth factor 1 (FGF1). This is recapitulated by FGF1 microinjection into the hypothalamic arcuate nucleus (ARC) and is accompanied by new synapse formation in this brain area. While these data invoke neural plasticity and neurocircuit remodeling as a potential mechanism for FGF1’s enduring anti-diabetic effect, how ARC plasticity is regulated in development and disease is unknown. Our lab studies developmental “critical period” plasticity in the ARC, how it is disrupted in genetic and acquired mouse models of T2D and obesity, and how neurocircuit remodeling in the ARC may be used to treat metabolic abnormalities in these models.
During critical periods (CPs) of early postnatal life, developing neurocircuits exhibit heightened plasticity and are shaped by environmental cues. The CP in visual cortex (V1) is a well-studied example: during the CP, but not before or after, visual deprivation of one eye induces a strong shift of neuronal responses to the non-deprived eye. While CP opening requires maturation of V1 inhibitory circuitry, closure depends on perineuronal nets (PNNs), extracellular matrix specializations that enmesh and thereby regulate the plasticity of key neurons in the circuit. Reactivation of CP plasticity in the adult brain, to restore acuity to a deprived eye, can be achieved in V1 by PNN digestion or by inhibitory interneuron transplantation. Recently, a CP has been defined for the maturation of ARC Agouti-related peptide (Agrp) neurons, which are implicated in control of both energy and glucose homeostasis. During this CP, the adipocyte hormone leptin provides a trophic signal that promotes the formation of projections from Agrp neurons to downstream targets in the circuit.
We have identified PNNs in the ARC, enmeshing Agrp neurons. These PNNs arise at weaning, following the lactation period when overnutrition can alter ARC projections to downstream targets and have lasting effects on adult metabolism. Our data shows ARC PNNs are deficient in postnatal leptin-deficient ob/ob mice, and paradoxically, in excess in adult ob/ob mice. Based on evidence linking early nutritional status to adult susceptibility to metabolic disorders, we hypothesize that nutritional and hormonal cues during this early period shape ARC circuits via PNNs, and that experimentally remodeling neurocircuits in the ARC in models of T2D and obesity may reset the defended levels for blood glucose and body fat to a more normal value. To this end, we employ a variety of in vivo stereotaxically-targeted manipulations aimed at modulating ARC plasticity in developing and adult models of T2D and obesity, with subsequent analysis using tools in metabolic phenotyping, electrophysiology, biochemistry, histology, and single-cell molecular profiling.
Lab Members
Read Bio
Shilpa Kommaraju, PhDPostdoctoral Fellow
Read Bio
Chelsea Faber, PhDPostdoctoral Fellow
Read Bio
Elaine CabralesResearch Technician
publications
- Mirzadeh et al., Perineuronal Net Formation during the Critical Period for Neuronal Maturation in the Hypothalamic Arcuate Nucleus. February 2019.
- Bentsen et al., Revisiting How the Brain Senses Glucose-And Why. January 8, 2019.
- Chen et al., Complication rates, lengths of stay, and readmission rates in “awake” and “asleep” deep brain simulation. August 2017.
- Mirzadeh et al., Bi- and uniciliated ependymal cells define continuous floor-plate-derived tanycytic territories. January 9, 2017.
- Mirzadeh et al., The rationale for deep brain stimulation in Alzheimer’s disease. July 2016.
- Scarlett et al., Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents. July 2016.
- Chen et al., “Asleep” deep brain stimulation for essential tremor. June 2016.
- Mirzadeh et al., Parkinson’s disease outcomes after intraoperative CT-guided “asleep” deep brain stimulation in the globus pallidus internus. April 2016.
- Turner et al., Fluctuations in Spinal Cord Perfusion During Adult Spinal Deformity Correction Identify Neurologic Changes: Proof of Concept. January 2016.
- Mirzadeh et al., Re: Letter to the editor regarding microelectrode recordings and deep brain stimulation surgery–Reasoned discussion?. August 2015.
- Mirzadeh et al., Reply: DBS with versus without MER: clinical equipoise or malpractice?. March 2015.
- Mirzadeh et al., Validation of CT-MRI fusion for intraoperative assessment of stereotactic accuracy in DBS surgery. December 2014.
- Mirzadeh et al., Predictors of functional recovery in adults with posterior fossa ependymomas. May 2014.
- Tong et al., Axonal control of the adult neural stem cell niche. April 3, 2014.
- Alfaro-Cervello et al., Biciliated ependymal cell proliferation contributes to spinal cord growth. October 15, 2012.
- Sanai et al., Corridors of migrating neurons in the human brain and their decline during infancy. September 28, 2011.
- Mirzadeh et al., The azygos anterior cerebral artery bypass: double reimplantation technique for giant anterior communicating artery aneurysms. April 2011.
- Sanai et al., Supracerebellar-supratrochlear and infratentorial-infratrochlear approaches: gravity-dependent variations of the lateral approach over the cerebellum. June 2010.
- Mirzadeh et al., The subventricular zone en-face: wholemount staining and ependymal flow. May 6, 2010.
- Guirao et al., Coupling between hydrodynamic forces and planar cell polarity orients mammalian motile cilia. April 2010.
- Mirzadeh et al., Cilia organize ependymal planar polarity. February 17, 2010.
- Jacques et al., Combinations of genetic mutations in the adult neural stem cell compartment determine brain tumour phenotypes. January 6, 2010.
- Mirzadeh et al., Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. September 11, 2008.
- Sanai et al., Functional outcome after language mapping for glioma resection. January 3, 2008.
- Adachi et al., Beta-catenin signaling promotes proliferation of progenitor cells in the adult mouse subventricular zone. November 2007.
- Merkle et al., Mosaic organization of neural stem cells in the adult brain. July 20, 2007.
- Kuo et al., Postnatal deletion of Numb/Numblike reveals repair and remodeling capacity in the subventricular neurogenic niche. December 15, 2006.
- Quiñones-Hinojosa et al., Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells. January 20, 2006.
resources
JOB OPENINGS
There are no job openings at this time.