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  • ABOUT
    • History
    • UAPA EXECUTIVE BOARD & COMMITTEES
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  • Postdoc Life
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Spotlight

Dr. Caroline Machado Kopruszinski- Dept. pf Pharmacology

4/29/2021

 
​As a post-doctoral fellow in the laboratory of Dr. Frank Porreca, my research has focused on studying orofacial pain.  My approach has been to use pharmacology, genetics and animal behavior. My professional goal is to establish a research program that focuses on the exploration of neural, immune and hormonal mechanisms that promote migraine pathophysiology disproportionally in women and to uncover mechanisms that can be exploited for the development of new therapies that will help patients suffering from this debilitating and often chronic condition.
Migraine is a common, disabling neurological disorder with a strong genetic component that impairs patients’ quality of life.  Currently available therapies are effective in less than half of people with migraine. During my post-doctoral period, I have published several studies on preclinical assessment of migraine and other underlying headache and craniofacial pain disorders with a goal of understanding mechanisms that may promote pain. One of the problems with preclinical studies of migraine is that we cannot replicate the genetic basis that underlies the human condition. For this reason, surrogate strategies have to be used to model the disorder mechanistically. I recently developed an injury-free model of migraine-like pain by evaluating the effect of inhalational exposure of umbellulone, an agonist at TRPA1 receptors that are found on afferent fibers innervating the cranial meninges.  Umbellulone is the major volatile constituent of Umbellularia californica, commonly known as the “headache tree”.  Anecdotal reports reveal that people with underlying primary headache disorders can develop migraine and cluster headache when exposed to the tree, likely from this volatile substance.  Importantly, however, people without headache disorders do not experience headache attacks with umbellulone suggesting a requirement for pre-existing vulnerability.  I approached this by subjecting mice to repeated episodes of stress, another known trigger of migraine, to induce vulnerability. Repeated episodes of stress induced a “sensitized” state in mice so that a normally subthreshold stimulus, i.e., umbellulone, now produced pain behaviors that were reminiscent of migraine-like pain. I then used this model to study possible mechanisms relevant to migraine and to investigate new anti-migraine therapies.  Using this model, I found that activation of the protease activated receptor 2 (PAR2) receptor could produce migraine-like pain in vulnerable animals and that systemic administration of a monoclonal PAR2 antibody could be an effective preventive migraine therapy. I am currently working with a major pharmaceutical company in their efforts to perform a clinical trial in migraine patients with this antibody.
Currently, I have been using genetically modified mice, CRISPR/Cas9 gene editing as well as opto- and chemogenetic methods to explore the peripheral and central neural circuits that can promote migraine pain and that might contribute to the sexually dimorphic nature of migraine. I have also focused on understanding of the neurobiology of the different phases of migraine, including especially the premonitory phase, which appears to be the critical period in which the pain attack begins and represents the transition point from the interictal phase.  Finding ways to extend the duration of the interictal phase would allow us to prevent the transition of episodic migraine to chronic migraine.
These experiences have led me to improve as a scholar and to become competitive for research funding.  I had the honor of receiving my first competitive extramural grant as a principal investigator in 2019. This year, I was delighted to receive an Honorable Mention from the review committee of University of Arizona Postdoctoral Affairs, as one of four finalists for the 2021 Outstanding Postdoctoral Scholar Award. The recognition and my collective experiences will increase my confidence in competing for future grants, aiding my transition to independent status as my career progresses.  My goal is to pursue studies of high significance that will be impactful in helping the overall efforts of the headache research community to improve therapy for patients with migraine, post-traumatic headache and other craniofacial pain disorders.As a post-doctoral fellow in the laboratory of Dr. Frank Porreca, my research has focused on studying orofacial pain.  My approach has been to use pharmacology, genetics and animal behavior. My professional goal is to establish a research program that focuses on the exploration of neural, immune and hormonal mechanisms that promote migraine pathophysiology disproportionally in women and to uncover mechanisms that can be exploited for the development of new therapies that will help patients suffering from this debilitating and often chronic condition.
Migraine is a common, disabling neurological disorder with a strong genetic component that impairs patients’ quality of life.  Currently available therapies are effective in less than half of people with migraine. During my post-doctoral period, I have published several studies on preclinical assessment of migraine and other underlying headache and craniofacial pain disorders with a goal of understanding mechanisms that may promote pain. One of the problems with preclinical studies of migraine is that we cannot replicate the genetic basis that underlies the human condition. For this reason, surrogate strategies have to be used to model the disorder mechanistically. I recently developed an injury-free model of migraine-like pain by evaluating the effect of inhalational exposure of umbellulone, an agonist at TRPA1 receptors that are found on afferent fibers innervating the cranial meninges.  Umbellulone is the major volatile constituent of Umbellularia californica, commonly known as the “headache tree”.  Anecdotal reports reveal that people with underlying primary headache disorders can develop migraine and cluster headache when exposed to the tree, likely from this volatile substance.  Importantly, however, people without headache disorders do not experience headache attacks with umbellulone suggesting a requirement for pre-existing vulnerability.  I approached this by subjecting mice to repeated episodes of stress, another known trigger of migraine, to induce vulnerability. Repeated episodes of stress induced a “sensitized” state in mice so that a normally subthreshold stimulus, i.e., umbellulone, now produced pain behaviors that were reminiscent of migraine-like pain. I then used this model to study possible mechanisms relevant to migraine and to investigate new anti-migraine therapies.  Using this model, I found that activation of the protease activated receptor 2 (PAR2) receptor could produce migraine-like pain in vulnerable animals and that systemic administration of a monoclonal PAR2 antibody could be an effective preventive migraine therapy. I am currently working with a major pharmaceutical company in their efforts to perform a clinical trial in migraine patients with this antibody.
Currently, I have been using genetically modified mice, CRISPR/Cas9 gene editing as well as opto- and chemogenetic methods to explore the peripheral and central neural circuits that can promote migraine pain and that might contribute to the sexually dimorphic nature of migraine. I have also focused on understanding of the neurobiology of the different phases of migraine, including especially the premonitory phase, which appears to be the critical period in which the pain attack begins and represents the transition point from the interictal phase.  Finding ways to extend the duration of the interictal phase would allow us to prevent the transition of episodic migraine to chronic migraine.
These experiences have led me to improve as a scholar and to become competitive for research funding.  I had the honor of receiving my first competitive extramural grant as a principal investigator in 2019. This year, I was delighted to receive an Honorable Mention from the review committee of University of Arizona Postdoctoral Affairs, as one of four finalists for the 2021 Outstanding Postdoctoral Scholar Award. The recognition and my collective experiences will increase my confidence in competing for future grants, aiding my transition to independent status as my career progresses.  My goal is to pursue studies of high significance that will be impactful in helping the overall efforts of the headache research community to improve therapy for patients with migraine, post-traumatic headache and other craniofacial pain disorders.
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Dr. Shio Kobayashi- Dept. of Immunobiology & BIO5 Institute

4/8/2021

 
I have been fascinated since I was an undergraduate by the human immune system, which in its elegance is both a fundamental and complicated system in our body. The system distinguishes the components of foreign pathogens or viruses from our self components and keeps up the pathogen surveillance. If pathogens or viruses invade our body, the immune system mobilizes immune cells and clears these invaders. The invader's information is relayed from cell to cell and is memorized in cells to respond quickly during a future attack, just like human society. But sometimes, this elaborate system mischaracterizes our self components as pieces of hostile foreigners and starts to attack our body. This abnormal condition is called 'autoimmunity'. The trigger of autoimmunity has not been clear despite big efforts by the researchers. 'Why our immune system attacks ourself? What happens in the immune system during an autoimmune disease?’. My journey into immune research is a quest to answer these simple yet profound questions.
 
I have learned immunology under the mentoring of Dr. Takeshi Watanabe and obtained my Ph.D. from Kyoto University in Japan. In my Ph.D. work, I focused on a type of T cells in rheumatoid arthritis (RA), which is one of the autoimmune diseases, and elucidated how T cells contribute to continuous inflammation at the local site in the patients by investigating RA patients’ samples. Through my Ph.D. work, the more I knew about a piece of the immune system, the more I was engrossed in immunology. I gradually desired to apply my knowledge and skills to the treatment of patients.

This passion drove me to work on the five modules CAR (5MCAR) project led by Dr. Michael S. Kuhns (University of Arizona, AZ) and Dr. Thomas Serwold (Joslin Diabetes Center, MA). The 5MCAR technology is based on the chimeric receptor (CAR) technology and aims to target pathogenic T cells. T cells expressing 5MCAR can eliminate only specific T cells via the receptor. We applied 5MCAR technology for the treatment of Type 1 diabetes (T1D), which is an autoimmune disease and is caused by pathogenic autoimmune T cells. Our data showed that 5MCAR expressing T cells eliminated only pathogenic T cells in T1D mouse models and prevented the onset of T1D in the mice. These results indicate that the 5MCAR technology has the potential for the treatment of not only T1D but also diseases caused by pathogenic T cells. We are now trying to apply the 5MCAR technology for the treatment of T-Lymphoma.
​
I have had a fulfilling research life at the University of Arizona under the mentorship of Drs. Kuhns and Michael Worobey, support from the university, especially the BIO5 Fellowship, and by Arizona's incredible culture. My journey into immune research is in its prologue. There is a long and rocky road ahead to answer my research questions and apply our technology to clinical studies. However, I am going to continue this scientific quest to impart my knowledge and skills to the patients diagnosed with autoimmune diseases.
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