PhD Research
August 2018-May 2023
Projects:Ubiquitin biochemistry, developing single-molecule biosensor for kinases, systems neuroscience evaluation of motor learning
Thesis: Developing effective and non-addictive analgesics has been a challenging endeavor for academics and pharmaceutical industry alike. This can partially be ascribed to the difficulty in developing preclinical assays that mirror the types of pain patients experience in the clinic-translational validity. The lab utilizes the mouse grimace scale, a behavioral assay that leverages changes in the facial expression of the mouse as a proxy of spontaneous/affective pain. This assay offers both translational and face validity, as known analgesics relieve facial grimacing in mice and grimacing is a routinely used pain behavioral measure in humans. While facial grimacing offers an excellent tool to examine a clinically relevant form of pain, spontaneous/affective, there remains limited integration of this assay in pain research programs due to the laborious nature of acquiring and processing of this data by highly trained individuals. To address this barrier in adoption, I have developed a scalable and automatable technology that integrates machine learning, engineering, optics, and affordable computing to acquire and process rodent grimacing data at scale. The technology offers a streamlined, efficient platform to explore the genetic and circuit mechanisms underlying spontaneous/affective pain and can be leveraged to discover novel, non-addictive analgesics. I leveraged this tool to identify strains of mice with divergent grimace responses, pharmacological screens, and to model empathy in rodents.
In addition to my work on pain, I was interested in exploring cortical-cell type composition across genetically diverse mice.
Projects:Ubiquitin biochemistry, developing single-molecule biosensor for kinases, systems neuroscience evaluation of motor learning
Thesis: Developing effective and non-addictive analgesics has been a challenging endeavor for academics and pharmaceutical industry alike. This can partially be ascribed to the difficulty in developing preclinical assays that mirror the types of pain patients experience in the clinic-translational validity. The lab utilizes the mouse grimace scale, a behavioral assay that leverages changes in the facial expression of the mouse as a proxy of spontaneous/affective pain. This assay offers both translational and face validity, as known analgesics relieve facial grimacing in mice and grimacing is a routinely used pain behavioral measure in humans. While facial grimacing offers an excellent tool to examine a clinically relevant form of pain, spontaneous/affective, there remains limited integration of this assay in pain research programs due to the laborious nature of acquiring and processing of this data by highly trained individuals. To address this barrier in adoption, I have developed a scalable and automatable technology that integrates machine learning, engineering, optics, and affordable computing to acquire and process rodent grimacing data at scale. The technology offers a streamlined, efficient platform to explore the genetic and circuit mechanisms underlying spontaneous/affective pain and can be leveraged to discover novel, non-addictive analgesics. I leveraged this tool to identify strains of mice with divergent grimace responses, pharmacological screens, and to model empathy in rodents.
In addition to my work on pain, I was interested in exploring cortical-cell type composition across genetically diverse mice.
Actin Remodeling During Conditions of Cellular Stress/C.elegans Drug Discovery
December 2014- August 2018
Advisor: Federico Sesti, PhD
The establishment and preservation of homoeostatic equilibria is critical for organismal growth and survival across phyla. For example, while organisms thrive at a wide range of external temperatures, slight and sudden increases in optimal temperature leads to heat shock (HS). HS is classically thought to impinge cell/organismal viability through protein misfolding that results in proteotoxicity. Yet, as evidence indicates, the effects of HS go beyond proteostatic injury. Indeed, one of the noncanonical substrates of HS is the actin cytoskeleton. HS disrupts filamentous actin (F-actin) networks by decreasing the cellular F-actin to globular actin (G-actin) ratio, effectively compromising cytoskeletal integrity. This collapse in F-actin stability occurs in both Caenorhabditis elegans and mammalian cells and correlates with decreased thermotolerance in both organisms. While F-actin collapse during HS is well established, the exact molecular mechanisms underlying this collapse were until recently unknown. I recently demonstrated that specific members of the Rho signaling modality, composed of small GTPases which regulate the cytoskeleton through actin binding proteins, compromise survival in C.elegans during HS through F-actin antagonism (Patel et al., 2017). I identified the C.elegans orthologs for the mammalian Rho GTPases CDC42 and RhoA as significant contributors to thermosensitivity in C.elegans. In addition, previous reports indicate acute exposure to mild HS, referred to as preconditioning (PC), enhances thermotolerance during full HS in C. elegans and murine neurons. Indeed, my findings demonstrate higher cytoskeletal integrity and corresponding survival in C. elegans exposed to PC relative no-PC controls following HS.
During my time in the Sesti lab, I also probed the utility of C.elegans as an intermediary assay between in vitro and in vivo pharmacology. This project resulted in a proprietary, provisionally patented drug screening platform that I am now validating in collaboration with multiple major US pharmaceutical companies. To pursue commercialization of this assay, Dr. Sesti and I were awarded an NSF Innovation Corps (I-Corps) award. This intensive 7-week, start-up like experience combined training in customer discovery, where I, as the entrepreneurial lead, met with over 100 leaders in the pharmaceutical industry, with mentorship from established entrepreneurs. Following graduation, I also worked on an NSF Program for Innovation-Technology Transfer grant (PFI-TT) that was eventually awarded to the Sesti lab for the validation of the assay, I now serve as a consultant for this grant.
Advisor: Federico Sesti, PhD
The establishment and preservation of homoeostatic equilibria is critical for organismal growth and survival across phyla. For example, while organisms thrive at a wide range of external temperatures, slight and sudden increases in optimal temperature leads to heat shock (HS). HS is classically thought to impinge cell/organismal viability through protein misfolding that results in proteotoxicity. Yet, as evidence indicates, the effects of HS go beyond proteostatic injury. Indeed, one of the noncanonical substrates of HS is the actin cytoskeleton. HS disrupts filamentous actin (F-actin) networks by decreasing the cellular F-actin to globular actin (G-actin) ratio, effectively compromising cytoskeletal integrity. This collapse in F-actin stability occurs in both Caenorhabditis elegans and mammalian cells and correlates with decreased thermotolerance in both organisms. While F-actin collapse during HS is well established, the exact molecular mechanisms underlying this collapse were until recently unknown. I recently demonstrated that specific members of the Rho signaling modality, composed of small GTPases which regulate the cytoskeleton through actin binding proteins, compromise survival in C.elegans during HS through F-actin antagonism (Patel et al., 2017). I identified the C.elegans orthologs for the mammalian Rho GTPases CDC42 and RhoA as significant contributors to thermosensitivity in C.elegans. In addition, previous reports indicate acute exposure to mild HS, referred to as preconditioning (PC), enhances thermotolerance during full HS in C. elegans and murine neurons. Indeed, my findings demonstrate higher cytoskeletal integrity and corresponding survival in C. elegans exposed to PC relative no-PC controls following HS.
During my time in the Sesti lab, I also probed the utility of C.elegans as an intermediary assay between in vitro and in vivo pharmacology. This project resulted in a proprietary, provisionally patented drug screening platform that I am now validating in collaboration with multiple major US pharmaceutical companies. To pursue commercialization of this assay, Dr. Sesti and I were awarded an NSF Innovation Corps (I-Corps) award. This intensive 7-week, start-up like experience combined training in customer discovery, where I, as the entrepreneurial lead, met with over 100 leaders in the pharmaceutical industry, with mentorship from established entrepreneurs. Following graduation, I also worked on an NSF Program for Innovation-Technology Transfer grant (PFI-TT) that was eventually awarded to the Sesti lab for the validation of the assay, I now serve as a consultant for this grant.
Deep Brain Stimulation (DBS) battery decay and longevity of Medtronic Activa Neurostimulatory Devices
December 2014- August 2018
Advisor: Eric L. Hargreaves, PhD
Deep Brain Stimulation (DBS) is an increasingly common adjunctive neurosurgical therapy implemented in conjunction with clinical management to treat movement disorders such as Parkinson’s Disease (PD), Essential Tremor (ET), and Dystonia, as well as psychiatric disorders such as major depression, obsessive compulsive disorder (OCD), and epilepsy. At the core of the DBS system remains the battery that powers the neurostimulator responsible for the therapeutic effects of the system, making the battery a quintessential element whose longevity and capacity influences clinical presentation and management of symptoms. The longevity of the neurostimulator battery has clinical importance as battery depletion has been linked to worsening of clinical symptoms. In our current study we aim to report the initial clinical data from the Acitva PC and SC implantations and replacements conducted at our institution through retrospective analysis of battery replacements. Along with providing initial clinical data on the longevity of these devices we are utilizing mathematical modeling to predict battery replacement of these devices; in turn clinicians may be better equipped to prevent end-of-battery-life associated clinical deterioration in patients with DBS
Advisor: Eric L. Hargreaves, PhD
Deep Brain Stimulation (DBS) is an increasingly common adjunctive neurosurgical therapy implemented in conjunction with clinical management to treat movement disorders such as Parkinson’s Disease (PD), Essential Tremor (ET), and Dystonia, as well as psychiatric disorders such as major depression, obsessive compulsive disorder (OCD), and epilepsy. At the core of the DBS system remains the battery that powers the neurostimulator responsible for the therapeutic effects of the system, making the battery a quintessential element whose longevity and capacity influences clinical presentation and management of symptoms. The longevity of the neurostimulator battery has clinical importance as battery depletion has been linked to worsening of clinical symptoms. In our current study we aim to report the initial clinical data from the Acitva PC and SC implantations and replacements conducted at our institution through retrospective analysis of battery replacements. Along with providing initial clinical data on the longevity of these devices we are utilizing mathematical modeling to predict battery replacement of these devices; in turn clinicians may be better equipped to prevent end-of-battery-life associated clinical deterioration in patients with DBS
Cultural framing and the problematics of diagnosis
March 2015- December 2015
Advisor: Joanna Kempner, PhD
Diseases are usually thought of as a biological phenomenon. However, physicians, pharmaceutical companies, patient advocates, and insurance companies increasingly play an important role in determining whether conditions are normal or abnormal, medical or not. In the 1970s, scholars such as Irving Zola, Peter Conrad, and Thomas Szasz, identified the process by which conditions become medical as medicalization. Since then, sociologists have written about the medicalization of various human conditions such as erectile dysfunction and hyperkinesis (now known as ADD). “Medicalization” has become an enormously influential and useful sociological concept. However, we believe that medicalization cannot explain the often-heated debates about the ontology of diagnoses that occur even after medicalization has occurred. These debates involve a process that Kempner and I have coined as “specification.” Our current study aims to elucidate this process through case studies of particular conditions/diseases in which this process is evident.
Advisor: Joanna Kempner, PhD
Diseases are usually thought of as a biological phenomenon. However, physicians, pharmaceutical companies, patient advocates, and insurance companies increasingly play an important role in determining whether conditions are normal or abnormal, medical or not. In the 1970s, scholars such as Irving Zola, Peter Conrad, and Thomas Szasz, identified the process by which conditions become medical as medicalization. Since then, sociologists have written about the medicalization of various human conditions such as erectile dysfunction and hyperkinesis (now known as ADD). “Medicalization” has become an enormously influential and useful sociological concept. However, we believe that medicalization cannot explain the often-heated debates about the ontology of diagnoses that occur even after medicalization has occurred. These debates involve a process that Kempner and I have coined as “specification.” Our current study aims to elucidate this process through case studies of particular conditions/diseases in which this process is evident.
Ataxia Telangiectasia Mutated (ATM) in the pathology of Alzheimer’s Disease
July 2014-December 2014
Advisor: Jianmin Chen, PhD
Cell cycle regulation and DNA damage repair are two fundamental processes crucial for proper cell function and development; if a cell cannot conduct accurate and efficient transcription it can lead to adverse phenotypic effects. These two processes are controlled by a multitude of genes, one of which is Ataxia Telangiectasia Mutated (ATM). Ataxia Telangiectasia (AT) is a rare neurodegenerative disease, affecting 1 in every 40,000 live births in the United States, in which the ATM gene is either inactivated or absent. As previously noted, ATM’s role in neuronal cycle regulation and DNA repair is crucial for proper cell function. Yet ATM’s role in other essential neuronal processes such as, spontaneous vesicle release, oxidative stress response, insulin release, long term potentiation, and inflammatory response, further highlighting the integral role of this protein. Due to the multifunctional and dynamic role ATM plays in the integral processes for proper neuronal function, and at large for proper brain function, it is the aim of the this study to elucidate the role of ATM in the development/progression of other neurodegenerative diseases. In particular, the goal of this study was to explore the role of ATM in the development/pathology of Alzheimer’s disease.
Advisor: Jianmin Chen, PhD
Cell cycle regulation and DNA damage repair are two fundamental processes crucial for proper cell function and development; if a cell cannot conduct accurate and efficient transcription it can lead to adverse phenotypic effects. These two processes are controlled by a multitude of genes, one of which is Ataxia Telangiectasia Mutated (ATM). Ataxia Telangiectasia (AT) is a rare neurodegenerative disease, affecting 1 in every 40,000 live births in the United States, in which the ATM gene is either inactivated or absent. As previously noted, ATM’s role in neuronal cycle regulation and DNA repair is crucial for proper cell function. Yet ATM’s role in other essential neuronal processes such as, spontaneous vesicle release, oxidative stress response, insulin release, long term potentiation, and inflammatory response, further highlighting the integral role of this protein. Due to the multifunctional and dynamic role ATM plays in the integral processes for proper neuronal function, and at large for proper brain function, it is the aim of the this study to elucidate the role of ATM in the development/progression of other neurodegenerative diseases. In particular, the goal of this study was to explore the role of ATM in the development/pathology of Alzheimer’s disease.
Stress of Sexual Aggression and its Effects on Neurogenesis and Learning
January 2014-July 2014
Advisor: Tracey J. Shors, Ph.D
Numerous studies have shown that stress affects females more negatively than males. Stress decreases neurogenesis for both sexes, but some studies show a sex difference on cell proliferation after exposure to a stressor (Falconer & Galea, 2003; Westenbroek et al., 2004). In our lab, we aim to pinpoint sex-specific measures and ameliorations in response to stress. Current studies in our lab focus on how exercise and stress consequently affects learning and neurogenesis. We have developed an animal model of sexual trauma and abuse called Sexual Conspecific Aggressive Response (SCAR). The SCAR model utilizes repeated exposure of a naïve pubertal rat to an opposite sex, sexually-aggressive adult male breeder conspecific rat, which results in sex-dependent affect and learning deficits during adulthood. It has been postulated that women are especially vulnerable to depression, post-traumatic stress disorders, and social phobias induced or exaggerated by early life stress (Kessler, et al 2003; Parker and Brotchie, 2010; Dalla and Shors, 2009). Thus, we hypothesize that female rats subjected to the SCAR paradigm will exhibit more profound neurobehavioral and neurophysiological deficits than female controls and male rats subjected to the SCAR paradigm. The development and characterization of an animal model of adolescent sexual abuse and understanding the molecular mechanism underlying the development of depression in this model will help identify a more effective treatment course for individuals who have suffered childhood abuse and experience symptoms of major depressive disorder as adults.
Advisor: Tracey J. Shors, Ph.D
Numerous studies have shown that stress affects females more negatively than males. Stress decreases neurogenesis for both sexes, but some studies show a sex difference on cell proliferation after exposure to a stressor (Falconer & Galea, 2003; Westenbroek et al., 2004). In our lab, we aim to pinpoint sex-specific measures and ameliorations in response to stress. Current studies in our lab focus on how exercise and stress consequently affects learning and neurogenesis. We have developed an animal model of sexual trauma and abuse called Sexual Conspecific Aggressive Response (SCAR). The SCAR model utilizes repeated exposure of a naïve pubertal rat to an opposite sex, sexually-aggressive adult male breeder conspecific rat, which results in sex-dependent affect and learning deficits during adulthood. It has been postulated that women are especially vulnerable to depression, post-traumatic stress disorders, and social phobias induced or exaggerated by early life stress (Kessler, et al 2003; Parker and Brotchie, 2010; Dalla and Shors, 2009). Thus, we hypothesize that female rats subjected to the SCAR paradigm will exhibit more profound neurobehavioral and neurophysiological deficits than female controls and male rats subjected to the SCAR paradigm. The development and characterization of an animal model of adolescent sexual abuse and understanding the molecular mechanism underlying the development of depression in this model will help identify a more effective treatment course for individuals who have suffered childhood abuse and experience symptoms of major depressive disorder as adults.