Dr. Sathish Venkatachalem is an Associate Professor for the School of Pharmacy at North Dakota State University. Dr. Venkatachalem’s lab focuses on lung diseases such as asthma, chronic obstructive pulmonary disorder, lymphangioleiomyomatosis, and pulmonary hypertension. This group is leading the research on elucidating the role of sex steroids in lung diseases like asthma. We were lucky enough to sit down with Dr. Venkatachalem to get his thoughts on the current state and future of asthma research!
A: My initial training during graduate school started with cardiopulmonary research with a background in calcium and contractility. This led me to do postdoc studies in Western Ontario on right heart failure and pulmonary hypertension relevant to calcium and contractility. It was at the move to Mayo Clinic that completely changed my research interests to Asthma and COPD. Now, thanks to my excellent training and mentors at Mayo Clinic, I have based my research in the pulmonary field. Specifically, on calcium and contractility and remodeling in asthma for the past 14 years.
A: I primarily focus on lung diseases like Asthma and COPD, with a particular emphasis on sex gender differences.
A: Relevant to my specific focus on sex-gender differences in asthma, the mechanistic basis to asthma concerning gender is not well understood. Sex steroid signaling are likely the main effectors probably for determining the effects of estrogen and testosterone in human airways.
The mechanistic basis for the sex-gender difference is not known in a long-term or short-term way. Asthma is a large spectrum of disease, and some spectrum of asthma is uncontrollable. The main question is can we target those who are not able to have maintenance therapy? That is the long-term goal.
A: In terms of asthma, the incidence is higher in both premenopausal women and aging men, suggesting the role of maybe estrogen. However, estrogen’s exact role with reference to inflammation and remodeling is not known and very complex, with a multicellular lung environment.
We study the effects of both hormones in different cellular levels. In addition to sex steroids, we are focusing on the upstream signaling of sex steroids. We are working on a protein called kisspeptin and its effects on the airway. Kisspeptins regulate the sex steroids, which play a role, and kisspeptins directly play a role too. So, we have a two-measure question to ask relating to the sex-gender difference in asthma.
A: We work with a mouse model of asthma, specialized in knock out models including smooth muscle-specific estrogen Receptor α/β KO and kisspeptin specific KO that we recently developed. We used genetic KO models along with pharmacological intervention to study sex differences in asthma.
In terms of asthma models, we use mixed allergen model of asthma, which includes ovalbumin, and extracts from Alternaria alternata, Aspergillus fumigatus, and Dermatophagoides farina.
A: We integrate our cellular model into our whole lung model. We need it in this pharmacological and physiological approach, and the therapeutic endpoint will be pharmacological therapy, as I am in the pharmacological science department now. We are developing a new small molecule pharmacological therapy for asthma towards gender-based therapy. This involves creating new small molecule inhibitors, antagonist, and agonist, for this specific sex-gender difference relevant to sex steroid receptor regulation. We believe using those small molecules that we are developing and interlacing the flexiVent, for lung function measures and airway hyperresponsiveness will be very insightful.
In our recent work, kisspeptin receptors agonist were shown to improve lung function using the flexiVent system in a mixed allergen model. To further stress these receptors’ role, a kisspeptin receptor antagonist worsens lung function even further in this mixed allergen model. These findings highlighted the importance of Kisspeptins as a potentially targetable system for novel therapeutics to reduce airway hyperresponsiveness and remodeling in asthma (Borkar, 2020).
A: The significant reward is finding novel findings in the research and getting new direction, publication and funding, and your own fellows/students’ success. I find research engaging all the time, with regards to new thought processes and new direction.
Always have a plan! Even if you are getting into academia or industry, these days, we need advanced planning. In reference to academia, prepare yourself one year ahead of time and make a list of what you need before you start. The first two years will be challenging, but if you plan correctly by hiring beforehand, working out with the students their plan, plan what instruments you need. There are always new faculty start-ups, and a lot of companies and resources are available to help. So use all the resources possible to make yourself comfortable – that is my advice.
A: In asthma, we are looking at irreversible remodeling and corticosteroid insensitivity causing some patients to not have the proper therapy or maintenance in asthma. The goal is to reduce airway remodeling and hyperresponsiveness by specifically targeting people who do not have the proper maintenance therapy.
We also recently published a paper looking into the possible gender differences in COVID-19, where we have come up with an idea of looking at the possible mechanisms and roles of sex steroid in COVID-19 (Kalidhindi, R., 2020). We explored estrogen vs. testosterone’s effects in modulating angiotensin-converting enzyme 2 (ACE2) expression, a cell entry point for COVID-19. We found intrinsic sex-steroid induces differences that explain the gender difference in incidence, severity, and mortality of the disease.
We also have in vitro data that we will be presenting soon, which show a promising role for kisspeptin-based approaches upstream of sex steroid – stay tuned!
Role of Estrogen Receptors α and β in a Murine Model of Asthma: Exacerbated Airway Hyperresponsiveness and Remodeling in ERβ Knockout Mice. (2020). Kalidhindi, R.S.R., … Sathish, V. Frontiers in Pharmacology, 10: 1499
Role of Differential Estrogen Receptor Activation in Airway Hyperreactivity and Remodeling in a Murine Model of Asthma. (2019). Ambhore, N.S., … Sathish, V. Americal Journal of Respiratory Cell and Molecular Medicine, 61(4)
Role of Kisspeptins in Airway Hyperresponsiveness and Remodeling in a Mouse Model of Allergic Asthma. (2020). Borkar, N.A.,… Sathish, V. ATS Journals, C60 Asthma: Cellular and Animal Models
Androgen Receptor-Mediated Regulation of Intracellular Calcium in Human Airway Smooth Muscle Cells. (2019). Kalidhindi, R.S.R.,… Sathish, V. Cellular physiology and biochemistry, 53(1): 215-228
Sex steroids skew ACE2 expression in human airway: a contributing factor to sex differences in COVID-19? (2020). Kalidhindi, R.S.R.,… Sathish, V. Lung Cellular and Molecular Physiology, 319(5): 843-847
Cellular and Biochemical Analysis of Bronchoalveolar Lavage Fluid from Murine Lungs. (2021). Kalidhindi, R.S.R.,… Sathish, V. Methods in Molecular Biology ;2223:201-215