Shobhan Gaddameedhi
Bio
Shobhan Gaddameedhi joined NC State in July 2020 as a Chancellor’s Faculty Excellence Program cluster hire in Environmental Health Science. He is an associate professor in the Department of Biological Sciences and director of the Circadian Clock and Genotoxic Stress Laboratory located in the Toxicology Building at Centennial Campus. He is a full member of the Toxicology Graduate Program and the Center for Human Health and the Environment (CHHE).
Gaddameedhi’s research focuses on three major areas on human health: unraveling the molecular basis of the circadian clock’s function in UV-DNA damage repair as it pertains to environmental health outcomes through ‘gene-environment’ interactions; understanding the mechanistic basis for genomic instability, cardiovascular toxicity, and skin carcinogenesis through circadian disruption by shift work; and understanding the effect of emerging environmental contaminants on circadian rhythmicity, sleep, genome integrity and carcinogenesis. Overall, the research from his lab will provide a mechanistic understanding of the biological clock’s role in “gene-environment” interactions and its impact on environmental disease prevention and therapeutic efficacy.
Gaddameedhi is a recipient of the 2013 National Institutes of Health (NIH)/National Institute of Environmental Health Sciences (NIEHS) K99/R00 Career Development Award, the 2018 Department of Defense/Congressionally Directed Medical Research Programs Career Development Award, and the 2020 NIH/NIEHS Outstanding New Environmental Scientist/ONES Award. In addition, Gaddameedhi is a recipient of the 2013 UNC Postdoctoral Award for Research Excellence, the 2018 American Society for Photobiology New Investigator Award and the 2018 Environmental Mutagenesis and Genomics Society Newly Independent Investigator Program Award.
Before joining NC State, he worked from 2014 to 2020 as an assistant professor of pharmaceutical sciences at Washington State University. Gaddameedhi received his master’s degree in plant sciences from the University of Hyderabad, India and his Ph.D. in pharmaceutical sciences from North Dakota State University. He then pursued his post-doctoral training in the circadian biology and DNA repair fields with Prof. Aziz Sancar at the University of North Carolina Chapel Hill from 2008 to 2014.
The outstanding neighboring research institutes (UNC, NIEHS, and Duke) drew Gaddameedhi’s interest back to working in the Research Triangle Park area. However, what solidified his resolve to return was the state-of-the-art research facilities, excellent supportive research environment, outstanding environmental health sciences faculty and colleagues, and interdisciplinary research programs present at NC State.
Publications
- Inspiring basic and applied research in genome integrity mechanisms: Dedication to Samuel H. Wilson , ENVIRONMENTAL AND MOLECULAR MUTAGENESIS (2024)
- A new role of TRPM8 in circadian rhythm and molecular clock , ACTA PHYSIOLOGICA (2023)
- Telomere dysfunction in Tert knockout mice delays BrafV600E-induced melanoma development , INTERNATIONAL JOURNAL OF CANCER (2023)
- The impact of shift-work light conditions on tissue-specific circadian rhythms of canonical clock genes: insights from a mouse model study , F1000Research (2023)
- The impact of shift-work light conditions on tissue-specific circadian rhythms of canonical clock genes: insights from a mouse model study , F1000Research (2023)
- The impact of shift-work light conditions on tissue-specific circadian rhythms of canonical clock genes: insights from a mouse model study [version 1; peer review: 1 approved, 1 approved with reservations] , F1000Research (2023)
- CIRCADIAN DYSREGULATION OF HUMAN DNA REPAIR GENES AND ELEVATED DNA DAMAGE IN SIMULATED NIGHT SHIFT SCHEDULE , Sleep (2022)
- Circadian disruption and cisplatin chronotherapy for mammary carcinoma , TOXICOLOGY AND APPLIED PHARMACOLOGY (2022)
- Circadian effects on UV-induced damage and mutations , MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH (2022)
- Endogenous Diurnal Patterns of Adrenal and Gonadal Hormones During a 24-Hour Constant Routine After Simulated Shift Work , JOURNAL OF THE ENDOCRINE SOCIETY (2022)
Grants
Circadian clocks respond to environmental time cues to coordinate 24-hour rhythmicity in gene expression and biological processes in virtually all cells of the body. According to the US Department of Labor, ~15-20% of Americans are engaged in rotating shift work, and the resulting altered timing of wake/sleep disrupts their endogenous circadian clock. Epidemiological studies have concluded that individuals who perform long-term rotating shift work suffer from an increased risk of several cancer types, including skin cancers. Skin cancer is the most common malignancy and its incidence is increasing dramatically in the U.S. Among the contributing factors, exposure to solar ultraviolet B (UVB) radiation is the major risk factor (up to 90%) for malignant transformation of skin cells and skin cancer development. In humans and mice, nucleotide excision repair (NER) removes genetic damage caused by UVB. Therefore, protection from UVB exposure and ensuring efficient NER capacity are critical for maintenance of genomic stability and prevention of skin cancer. Previous studies using genetic mouse models have shown that the circadian clock regulates several tumor suppressing pathways, including NER, that are critical for preserving genomic stability and protection against environmental carcinogenesis. However, there is a fundamental gap in understanding how circadian disruption associated with rotating shift work leads to environmental carcinogenesis and in the underlying molecular mechanisms that influence disease progression in humans. This lack of knowledge is an important roadblock because it highlights the need for mechanistic insight into malignant transformation and represents a barrier to predicting the severity of disease outcomes in shift workers. The overall objectives of this project are to identify and characterize early stage carcinogenesis mechanisms and consequences of circadian disruption in UVBinduced skin carcinogenesis. Our central hypothesis, supported by preliminary data, is that circadian disruption undermines DNA repair capacity, inflammatory responses, and other genotoxic stress-related cellular pathways that underlie the carcinogenicity of shift work. Our studies use circadian synchronized skin cells in vitro, circadian-disrupted and skin carcinogenesis-prone SKH-1 genetic mouse models in vivo, and skin samples from human subjects in vivo. In Aim 1, we will determine how the circadian rhythm impacts solar UVB radiation-mediated DNA damage responses including DNA repair and inflammatory responses. Theexperiments described in Aim 2 will examine how clock disruption by rotating shift work influences circadianrhythmicity and NER. In Aim 3, we will characterize how rotating shift work and genetic disruption of the circadian clock influence skin cancer initiation and progression. Collectively, the outcomes from these studies will provide a molecular roadmap of circadian disruption in UVB radiation-mediated genomic instability and carcinogenesis and will lead to the identification of novel mechanisms that can be applied toward disease prevention in individuals with abnormal circadian function.
Despite improvements in the precision of targeted cancer therapy, there are still significant risks of off-target effects that impact patient health and overall quality of life. Cardiotoxicity, for example, is a major concern for treatments like ionizing radiation (IR) and anthracycline chemotherapeutics, with long-term damage leading to heart failure. Novel strategies like chronotherapy have been implemented to maximize treatment efficacy and limit side effects; however, the mechanisms driving favorable outcomes are poorly understood. The principle behind chronotherapy is to harness the 24-hour oscillatory program of gene expression controlled by the circadian rhythm. At certain times of the day, circadian-regulated elements of DNA repair are more efficient in resolving DNA damage. Utilizing this concept, this project seeks to investigate how key circadian clock protein BMAL1 impacts the response of human cardiomyocytes to IR and doxorubicin (DOX). Based on our recently published data and preliminary findings in this proposal, we hypothesize that BMAL1 plays a protective role in cardiomyocytes via pathways of DNA damage repair and cell death against IR and DOX. To test our hypothesis, we will assess BMAL1????????s role in DNA damage response through ChIP-Seq, RNA-Seq, and Western blotting following IR and DOX treatment. We will also evaluate this system without direct cytotoxic insult using an IR-treated plasmid reporter to assess rates of double-strand (ds) DNA break repair under modified BMAL1 expression. Overall, this proposal will provide a novel mechanism for improved chronotherapy outcome.
Shift work, which is regularly experienced by millions of individuals (approximately 25% of the US workforce), is associated with increased risk of cancer, cardiovascular disease, metabolic disorders and neurodegenerative diseases. Evidence from our group and others indicate that disruption of the biological clock is a major environmental contributing factor to carcinogenesis. Yet, the underlying mechanisms are not well understood, which hampers efforts in prevention and mitigation of these devastating health risks. Although epigenetic modification of DNA is considered as one of the hallmarks of carcinogenesis, its connection with human circadian clock disruption and shift work is little known. The next logical step is to determine changes to differentially methylated regions (DMRs) and their role in DNA damage repair to identify molecular mechanisms, and search for biomarkers in order to better understand the environmental disease etiology. We must first ascertain whether simulated shift work induces epigenetic modification of DNA - one of the hallmarks of cancer. This will be executed by comparing 24 hour changes in DMRs of the whole genome, core clock genes, DNA damage repair genes, and other cancer hallmark genes in 14 simulated night and day shift workers. We will then be able to determine possible molecular mechanisms involved in elevated cancer risk as well as identify biomarkers and potential targets for treatment in real-world night shift workers.
Night shift workers are at increased risk of breast, prostate, lung, colon, bladder, rectal, and pancreatic cancer, as well as non-Hodgkin??????????????????s lymphoma. While considerable resources are allocated nationwide to gain a better understanding of how biological and behavioral factors affect cancer-related health, only a tiny fraction thereof is devoted to night shift work ?????????????????? a documented, influential factor that would be readily amenable to intervention and mitigation. With approximately 15% of the US work force engaged in non-traditional work hours, elevated risk of cancer is one of multiple factors causing considerable health disparities specific to shift work populations. Although resources are needed to address the carcinogenic aspect of shift work, the societal return on investment in terms of productive life years gained and health care costs saved would be staggering, as would be the potential to prevent or mitigate disease and suffering. Based on strong preliminary data (see below) and a track record of successful implementation of the experimental and diagnostic tools we plan to use, we therefore propose to elucidate the molecular underpinnings of night shift work as a carcinogen in real-world, active shift work populations. This will allow us to identify candidate biomarkers of elevated cancer risk and candidate molecular targets for the development of novel treatments with high potential for subsequent translation to clinical practice. Dr. Gaddameedhi is a leading expert on circadian disruption and the molecular underpinnings of carcinogenesis, and he will oversee the blood sample analyses at molecular aspects of the assays.
Melanoma is the most lethal form of skin cancer, due to its predilection for early metastasis, and is often associated with a poor prognosis due to resistance to therapy. Despite the promise of immunotherapy, less than 50% of melanoma patients respond to monotherapy or combination therapy with targeted therapy. Although, radiation therapy (RT) plays a small role in the traditional management of metastatic melanoma for palliation, recent experimental and clinical evidence suggests a broader involvement of RT in enhancing tumor cell killing in immunotherapy by augmenting the patient??????????????????s immune system. According to ClinicalTrials.gov, there are currently 109 active clinical trials underway for treatment of melanoma patients with radiation therapy (RT), mostly in combination with targeted/immunotherapy. However, the majority of patients that receive RT suffer skin inflammation ranging from mild erythema to ulceration. This side effect limits the dosages of radiation that can be administered, often to the point of terminating therapy early in order to prevent patient discomfort, which in turn increases the risk of redeveloping tumors and those tumors being resistant to further treatment. Understanding the circadian clock in healthy skin and melanoma may lead to prevention of these outcomes by minimizing skin toxicity and by improving tumor cell killing from RT in combination with immunotherapy. The circadian clock maintains daily rhythms in an organism, and the expression levels of many genes are controlled by oscillations of the circadian clock. The objective of this proposal is to translate our findings on the circadian clock control of RT mediated cellular toxicity and the immune system to patient benefit by minimizing skin toxicity and improving treatment efficacy in melanoma patients. Our hypothesis is that the circadian clock influences both tumor shrinkage and healthy tissue toxicity resulting from RT in combination with immunotherapy. We specifically seek to determine: how circadian rhythms impact RT mediated tissue toxicity and immune response in healthy tissues and melanoma tumors in genetic mouse models; and the impact of the circadian clock on efficacy of RT in combination with immunotherapy in melanoma-prone genetic mouse models. If awarded, this funding will help improve our mechanistic understanding of melanoma treatment. The successful completion of this study will lay a solid foundation for the next phase of the project, which will involve identifying how the circadian clock can be harnessed to improve efficacy and minimize toxicity of radiotherapy followed by immunotherapy. My career development plan facilitates these goals by focusing on interacting and collaborating with experts in cancer, immunotherapy, and radiation biology; forging new connections at conferences and workshops; and continuing to propose projects for extramural funding. In the long term, our research has the potential to benefit not only melanoma patients, but any cancer patient receiving radiation therapy as well as immunotherapy, by reducing the toxic side-effects and improving efficacy of their treatment. The end results of our research will lead to improved efficacy of radiation treatment through resetting of the patient circadian rhythm. Although this is not a clinical trial that will lead to immediate patient outcomes, this study will lay the groundwork for clinical trials that could be rapidly implemented, allowing us to understand the influence of the circadian rhythm on skin toxicity, especially radiodermatitis, and the immune system at the molecular level. This knowledge will help medical professionals better tailor their treatments to their patients?????????????????? biological rhythms. This research is particularly relevant to military personnel because the incidence of melanoma in active duty personnel has been increasing and is now higher than in the general population.
Shift work, which is regularly experienced by millions of individuals (approximately 15% of the US workforce), is associated with increased risk of cancer. Evidence from our group and others indicate that disruption of the biological clock is a major contributing factor. Yet, the underlying mechanisms are not well understood, which hampers efforts in prevention and mitigation of this devastating health risk. Our preliminary data show that shift work schedules induce increased DNA damage and alter 24-hour rhythms in the cellular expression of molecular clock genes and DNA damage repair genes. DNA damage and repair mechanisms thus become misaligned, which enhances genomic instability and may underlie the elevated cancer risk in shift workers. The next logical step is to identify molecular mechanisms, determine biomarkers of misalignment between DNA damage and repair processes, and search for molecular targets to develop novel treatments. However, we must first ascertain that our preliminary data pertain to real-world shift work populations. Therefore, in a combined field/laboratory study design, we will investigate the 24-hour expression patterns of clock genes, DNA damage repair genes, cancer hallmark genes, and markers of DNA damage in 34 active night and day shift workers. By comparing the night and day shift workers, we will document the molecular mechanisms involved in elevated cancer risk, identify biomarkers and candidate treatment targets in real-world night shift workers.
The telomerase gene (TERT) is a main target of mutations in both acral lentiginous melanoma (AM) and cutaneous melanomas (CM). One difference between AM and CM is that AM tumors display more chromosomal aberrations, including those at the hTERT locus. We reported that hTERT activation via chromosomal rearrangement occurred during telomere deficiency-induced crisis in human fibroblasts, and will determine if a similar process occurs in AM and CM. Moreover, polymorphisms at the hTERT locus may impact telomere homeostasis and chromosomal stability as well as genetic susceptibilities to AM and CM. Our hypothesis is that telomere-induced chromosomal instability promotes hTERT activation and the progression of acral melanoma. The project will be led by Ors. Robertson and Zhu, with expertise in melanoma and telomere biology, respectively. These senior investigators have paired up with junior investigators, Dr. Gowda (animal model and nanoparticle expertise) and Dr. Cheng (stem cell biology expertise) to accomplish this project. We will (1) unravel regulation of wildtype and cancer-specific mutant hTERT promoters in AM, CM, and normal melanocytes, using a novel BAC reporter model; (2) determine telomere length in AM, CM, and melanocytes and identify its role in melanoma stem cell-like plasticity; (3) determine the impact of polymorphisms at the hTERT locus on genetic predispositions to AM and CM; (4) determine the impact of telomere deficiency on melanoma development and drug responses in mouse models. Successful achievement of this project will develop unique models to study the TERT gene in melanoma etiology and develop novel approaches to modulate these diseases. DocuSign Envelope ID: FA50C811-4009-49B5-90A7-C67EFD483777