The McKnight Brain Institute is pleased to congratulate our 2015 Fellowship Awardees
The MBI Fellowships were established to support students and fellows conducting neuroscience and brain-related research in MBI affiliated laboratories. Two winners were selected and will each receive $60,000 ($30,000/year for two years). Three runner-ups were also selected and will each receive $30,000 ($15,000/year for two years).
Pre-Doctoral Fellow Awardee: Michael Massengill, Department of Molecular Genetics and Microbiology
Mentor: Dr. Alfred Lewin
AAV2 Delivery of an Nrf2 Derived Peptide to Enhance Neuroprotection in Autosomal Dominant Retinitis Pigmentosa
Retinitis pigmentosa (RP) represents a group of retinal neurodystrophies that are caused by defects in over 60 genes and collectively affect 1 in 4,000 individuals. At present, there is no cure for RP. Because of the relatively benign symptomatology that occurs in the early stages of RP, patients often present for treatment late in the disease course only after the initiation of secondary cone degeneration. This is the stage of RP that leads to complete blindness and typically compels patients to seek therapy; therefore identifying treatments that slow cone degeneration would maximize the patient population that can benefit from an intervention. The current goal of the field is to create a generic therapeutic strategy whose mechanism of action is independent of the inciting mutation. The notion that diverse disease-causing mutations result in the same RP phenotype strongly suggests that the secondary cone degeneration occurs via a common pathway independent of the initiating mutation. Based on several lines of evidence, our laboratory hypothesis is that oxidative stress contributes to cone cell death and therefore represents a generic therapeutic target. Therefore, the goals of our research program are: 1) to determine the role for oxidative stress in RP by using transgenic animal models of this disease, and 2) to test a novel gene therapy strategy that augments the retinal antioxidant response by enhancing Nrf2 signaling for the treatment of RP caused by mutations in rhodopsin. Because the retina is an extension of the CNS, our work could be significant to other CNS diseases with an oxidative stress component such as ALS and intracerebral hemorrhage.
Pre-Doctoral Fellow Runner-up: Danielle Sambo, Department of Neuroscience
Mentor: Dr. Habibeh Khoshbouei
Sigma-1 receptor modulation of methamphetamine-induced behavioral responses and neuronal adaptations of dopaminergic neurons
Methamphetamine (METH) addiction is a major public health issue, with no effective FDA approved treatment options. METH is a highly addictive drug that has been shown to disrupt dopamine neurotransmission in the brain. Current reports support the interpretation that METH-induced neuronal injury may render METH users more susceptible to neurodegenerative pathologies such as Parkinson like symptoms or schizophrenia. The goal of this project is to identify target specific pharmacotherapies to alleviate the untoward consequences of METH. Recently an intracellular target for METH called the sigma-1 receptor (σ1R) has been identified. The σ1R is a chaperone protein that is activated by different ligands in an agonist-antagonist manner. Upon activation, the σ1R has been shown to regulate a variety of cellular functions and is considered to be neuroprotective in the brain. Interestingly, several σ1R ligands have been shown to reduce the behavioral effects of METH in rodents; however, the mechanism is largely unknown. Preliminary in vitro data in our lab suggest that the activation of the σ1R attenuates METHmediated changes in dopamine neurotransmission. The focus of this current study is to investigate the role of the σ1R in METH-mediated behavioral responses and activity of dopaminergic neurons in the brain. These findings will expand on our current findings that σ1R activation decreases METH-mediated dopamine neurotransmission. Through the completion of these studies, we are poised to determine whether σ1R is a potential therapeutic target for the treatment of METH addiction, and the long-term untoward consequences of METH.
Post-Doctoral Fellow Awardee: Kaustuv Saha, Department of Neuroscience
Mentor: Dr. Habibeh Khoshbouei
How does alpha-synuclein regulate the excitability of dopamine neurons?
The greatest challenges in treatment of neuropsychiatric and neurodegenerative diseases, where brain dopamine levels are dysregulated, are to determine the underlying molecular mechanisms and to develop therapies addressing such mechanisms. Current therapies for Parkinson’s disease do not change the nature of the disease; they are shortlived and provide symptomatic relief. The long-term goal of this project is to understand the process of disease progression, which is required for the identification of disease-modifying therapies. One of the hallmarks of Parkinson’s disease is increased level of a protein called alpha-synuclein (a-syn). A-syn is found in Lewy bodies containing a-syn fibrillary aggregates. Limited information is available on how pathological levels and forms of a-syn affect neuronal activity in general and dopaminergic neurons in specific. Under the mentorship of Dr. Habibeh Khoshbouei, I will be using patch-clamp electrophysiology, live cell microscopy and biochemical approaches to determine how various forms of a-syn influence the activity of mouse midbrain dopamine neurons and iPSC-derived human-like dopamine neurons obtained from a patient with Parkinson’s disease and a healthy control. The results of this work will help us to understand the process of disease progression that can lead to identification of diseasemodifying therapeutic targets for the treatment of Parkinson’s disease.
Post-Doctoral Fellow Runner-up: Luis Colon-Perez, Department of Psychiatry
Mentor: Dr. Marcelo Febo
Perinatal Cannabis Smoke Exposure and Development of Brain Network Connectivity
Brain development in early stages of life is critical for long-term stability of functional and structural brain networks (i.e. the connectome). Abnormal functional and structural connectivity patterns have been measured in a number of disorders involving cognitive deficits, mood instability, and severe psychiatric diseases. Therefore, a stable connectome from early development to young adulthood may be vital to future cognition and emotion. Exposure to high levels of marihuana smoke during neonatal development through 2nd hand inhalation could alter neurodevelopment trajectories. However, investigating the effects of cannabis smoke on connectome development by exposing newborn infants to cannabis is impossible due to obvious ethical and major health reasons. Animal studies are thus important and needed to gain an understanding of the effects of cannabis smoke on brain connectome development and its lasting behavioral and neurobiological effects. In this study I will investigate the effects of cannabis smoke exposure during the perinatal period on structural connectivity and investigate the effects of cannabis smoke exposure during the perinatal period on functional connectivity. It is predicted that structural connectivity alterations will lead to alterations in functional connectivity. The expected changes in BOLD signals will translate into measurable changes in network connectivity in rats. This work is expected to generate markers of cannabis use during development that can be translated into human studies.
Adj. Clinical Post Doc Fellow Runner-up: Leli Shahgholi, Department of Neurology & UF CMDNR
Mentor: Dr. Michael Okun
An Antidote for Botulinum Neurotoxin/A
Botulinum neurotoxins (BoNTs) are the most poisonous substances known, and it is estimated that 1 gram of purified toxin could kill more than 1 million people. BoNTs are involved in a number of preferred treatments for managing dystonia, limb spasticity, cosmetic glabellar lines, hyperhidrosis, and sialorrhea. Once Botox (BoNTs) are absorbed following administration, it becomes difficult to reverse their action, and side effects including swallowing difficulties may persist for weeks to months. This project aims to develop a Botox antidote to restore neurotransmission and alleviate the neurotoxicity associated with BoNT intoxications