Colleagues: Recently Tenured

Meet your recently tenured colleagues: Yeka Aponte (NIDA, pictured), Haiming Cao (NHLBI), Marc Ghany (NIDDK), Stavroula (Voula) Mili (NCI-CCR), and Naoko Mizuno (NHLBI).

YEKA APONTE, PH.D., NIDA

Senior Investigator and Chief, Neuronal Circuits and Behavior Section, National Institute on Drug Abuse

Education: Universidad Central de Venezuela in Caracas, Venezuela (B.Sc. in biology); University of Freiburg in Freiburg, Germany (Ph.D. in natural sciences)

Training: Postdoctoral training at the University of Freiburg and the Janelia Research Campus, Howard Hughes Medical Institute (Ashburn, Virginia)

Came to NIH: In 2013 as an Earl Stadtman Tenure-Track Investigator

Outside interests: Traveling the world; learning about different food cultures; preparing elaborate meals; hiking; and watching soccer

Website: https://irp.nih.gov/pi/yeka-aponte

Research interests: Obesity and opioid overuse are global epidemics and major causes of death. Public awareness of the addictive properties of food and opioids has been growing progressively throughout the last decade. Both overeating and substance overuse are disorders by which individuals learn rewarding associations between stimuli (such as highly palatable foods and opioids) and outcomes.

My laboratory is investigating how specific neurons modulate the rewarding and addictive nature of food and opioids. We study this topic at the level of neuronal circuits in the context of behaviors, cell types, and synaptic connectivity. Using the mouse as our model system, we apply optogenetics and chemogenetics to manipulate neuronal circuits in awake, behaving mice. In addition, we use a combination of electrophysiology, fluorescence endomicroscopy, and behavioral assays to elucidate the neuronal basis of survival behaviors, such as feeding and nociception (detection of painful stimuli), and determine how these behaviors are disrupted in both eating and substance-overuse disorders.

Recently, we found that neurons in the brain’s lateral hypothalamic parvalbumin region orchestrate pain behaviors in mice. We demonstrated their potential as a novel target for analgesic treatment (Elife 10:e66446, 2021). In addition, we found that certain lateral hypothalamic GABAergic neurons that express leptin receptors drive appetitive behaviors in mice (Cell Rep 36:109615, 2021). In another study, we manipulated three hypothalamic neuronal populations that had well-known effects on feeding and found that each type had distinct—and sometimes unexpected—effects on food consumption and reward. The complexity of hypothalamic feeding regulation can be used as a framework to characterize how other neuronal circuits affect hunger and help us identify potential therapeutic targets for eating disorders (Curr Biol 31:3797-3809.e5, 2021).

Ultimately, understanding the mechanisms regulating food intake and the rewarding and addictive nature of food will enhance our ability to battle disorders such as obesity, diabetes, anorexia, bulimia, and substance overuse.

HAIMING CAO, PH.D., NHLBI

Senior Investigator, Laboratory of Obesity and Metabolic Diseases, National Heart, Lung, and Blood Institute

Education: Harbin Normal University in Harbin, China (B.S. in biology; M.S. in genetics); University of Nevada in Reno (Ph.D. in biochemistry)

Training: Postdoctoral training at the School of Public Health, Harvard University (Boston)

Came to NIH: In 2011 as a Stadtman Investigator in NHLBI

Outside interests: Reading about history, philosophy, and culture

Website: https://irp.nih.gov/pi/haiming-cao

Research interests: The worldwide obesity epidemic—along with an array of obesity-related disorders, particularly diabetes, fatty liver, and cardiovascular diseases—has become a major public health threat in the 21st century. The molecular and pathological basis by which obesity induces metabolic disorders, however, remains only partly understood, hampering the development of effective therapies against these debilitating diseases.

My group is studying the complex regulation of energy metabolism and uncovering its significance in metabolic physiology and the pathogenesis of metabolic disease. Our current knowledge of energy metabolism is mostly based on studies of protein-coding genes, which constitute less than 2% of the human genome. Examinations of the human transcriptome in recent years have revealed that over 85% of the human genome is transcribed, and human cells express tens of thousands of long, noncoding RNAs (lncRNAs). In humans, lncRNAs are at least three times as prevalent as protein-coding genes, and many lncRNAs overlap disease-associated genetic variants, suggesting that they might have important physiological functions.

We demonstrated that a large number of lncRNAs could function as vital metabolic regulators in mice (Cell Metab 2:455-67, 2015; Cell Rep 14:1867-187, 2016; and Cell Metab 24:627-639, 2016). Our findings also suggest that energy metabolism-associated lncRNAs may have systemic regulatory effects, and that the dysregulation of these lncRNAs could be the underlying cause of many metabolic abnormalities.

We recently produced humanized mice in which the mouse liver cells are replaced by human hepatocytes (essentially, these mice carry a human liver). Using this powerful model, my lab has demonstrated that many human-specific lncRNAs regulate critical signaling networks in human metabolism and their dysregulation could play a role in the pathogenesis of human metabolic diseases (Nat Commun 11:45, 2020; and J Clin Invest 131:e136336, 2020).

MARC GHANY, M.D., M.H.SC., NIDDK

Senior Investigator and Chief, Clinical Hepatology Research Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases

Education: Royal College of Surgeons in Ireland, Dublin, Ireland (M.D.); Duke University, Durham, North Carolina (M.H.S. in clinical research)

Training: Residency in internal medicine at Hospital of Saint Raphael (New Haven, Connecticut); fellow, gastroenterology and hepatology, Tulane University (New Orleans)

Before coming to NIH: Clinical instructor in gastroenterology and hepatology, Department of Medicine, Tulane University

Came to NIH: In 1996 as medical staff fellow in NIDDK; in 2000 became a staff physician, Liver Diseases Branch, NIDDK; became tenure-track investigator in 2015

Outside interests: Enjoys cycling, sailing, and cooking

Website: https://irp.nih.gov/pi/marc-ghany

Research interests: My career has centered on understanding the natural history and therapy of the hepatitis B and C viruses. These two viruses are major causes of cirrhosis and liver cancer. My clinical and translational team examines how the host, viruses, and environment interact to affect infection outcomes. We perform translational studies in the laboratory and conduct clinical trials to evaluate novel ways to manage or cure these chronic viral infections. Through my research, I am trying to understand how certain therapies work or why they fail and identify new treatment approaches. The ultimate goal is to improve the care and outcomes of patients with chronic viral hepatitis.

Specifically, my research focuses on 1) defining the host, viral, and environmental factors that determine the natural history and outcome of hepatitis B and C infections; 2) developing and evaluating novel, more effective therapies for chronic viral hepatitis B and C; and 3) understanding mechanisms of action of therapy and predictors of treatment response.

We demonstrated that, in patients with chronic hepatitis C, the innate immune system contributes to a successful response to direct-acting antiviral therapy (Hepatology 68:2078-2088, 2018). For chronic hepatitis B, new biomarkers are needed to better stratify risk and select patients for therapy. In a recent multinational consortium study, we tested two biomarkers and compared them to conventional biomarkers of hepatitis B virus replication and disease activity. We found that the novel markers offered limited advantages over currently approved assays in characterizing the phase of chronic hepatitis B but may have a role in assessing the efficacy of antiviral agents that are being developed (Hepatology 74:2395-2409, 2021).

Further research on chronic hepatitis C will involve collaborations to define the clinical, virological, histological, and immunological outcomes following cure of the disease. Additional research on chronic hepatitis B will require conducting clinical trials to evaluate novel more effective therapies.

STAVROULA (VOULA) MILI, PH.D., NCI-CCR

Senior Investigator, Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute

Education: National Kapodistrian University, Athens, Greece (B.Sc. in biology); Mount Sinai School of Medicine of New York University, New York (Ph.D. and M.Phil. in biomedical sciences)

Training: Postdoctoral training, Yale University (New Haven, Connecticut) and University of Virginia (Charlottesville, Virginia)

Came to NIH: In 2012 as a Stadtman Investigator

Outside interests: Figuring out how to raise two boys; trying to stay fit with minimal effort

Website: https://irp.nih.gov/pi/stavroula-mili

Research interests: I am studying RNA localization—how and why cells transport specific messenger RNAs (mRNAs) to predetermined locations. A large fraction of mRNAs do not distribute diffusely in the cytoplasm of cells but adopt a variety of distribution patterns through passive or active transport to a variety of subcellular destinations. The roles fulfilled by these intricate localization mechanisms are largely unknown.

My group has spearheaded the study of mRNAs that are targeted to protrusive regions of migrating mammalian cells. This protrusion-localization pathway is controlled by disease-related factors such as the tumor-suppressor protein APC, whose mutation or loss initiates the majority of colorectal cancers, and the FUS protein, which is mutated in cases of amyotrophic lateral sclerosis and other neurodegenerative diseases (Nature 453:115-119, 2008; J Cell Biol 216:1015-1034, 2017).

Our research is revealing that mRNA location can provide a partner-selection mechanism for proteins that can engage with multiple, mutually exclusive interacting partners. In such cases, the specific location of the mRNA and co-translational events that happen at the site of synthesis provide important determinants for selecting among multiple potential partners and thus for specifying the functional potential of the encoded protein (EMBO J 39:e104958, 2020).

We are investigating the physiological relevance of these mechanisms in normal tissue function and in the context of cancer metastasis, and we are examining their broader implications regarding the regulation of protein function.

NAOKO MIZUNO, PH.D., NHLBI

Senior Investigator, Laboratory of Structural Cell Biology, National Heart, Lung, and Blood Institute

Education: University of Tokyo (B.S. in pure and applied sciences; M.S. in life sciences); University of Tokyo and University of Texas Southwestern Medical Center in Dallas, Texas (Ph.D. in biophysics)

Training: Research fellow, NIAMS

Came to NIH: In 2007-2011 as research fellow; returned to NIH as Stadtman Investigator in 2020

Before returning to NIH: Independent Group Leader, Max Planck Institute of Biochemistry (Martinsried, Germany)

Outside interests: Traveling; building furniture

Website: https://irp.nih.gov/pi/naoko-mizuno

Research interests: My lab was initiated in 2012 at the Max Planck Institute of Biochemistry and relocated to NIH (NIAMS-NHLBI joint appointment) in 2020. We are investigating the molecular mechanisms governing specialized cell shapes, such as those of neurons, activated immune cells, platelets, and certain cancer cells. We use several techniques—in situ cellular cryoelectron tomography in combination with interdisciplinary techniques such as single-particle cryoelectron microscopy, X-ray crystallography, in vitro reconstitution, and cellular light microscopy—to visualize the key factors determining different cell morphologies.

We are elucidating the molecular actions of how neurons are created. These highly polarized cells form an intricate network of dendrites and axons. In one study, using primary neuronal cell cultures from hippocampus and thalamus explants of mouse embryos, we obtained a roadmap of events showing local protein synthesis selectively taking place at axon branches, allowing them to serve as unique control hubs for axon development and downstream neural network formation (J Cell Biol 4:221(4):e202106086, 2022).

We are also exploring precise mechanisms of how the involved molecular players crosstalk with each other in order to define cell shape. By doing so, we can find molecular clues for cellular defects. We use a technique, which we call “bottom-up analysis,” to elucidate how building blocks regulate themselves or each other in a binary or synergistic fashion at a molecular resolution. This strategy helped us to solve several functional mysteries in cellular homeostasis (Science Adv 7:eabe9716, 2021; elife 9:e56110, 2020; Cell 179:120-131.e13, 2019; Nat Commun 9:4684, 2018; Nat Cell Biol 20:1172-1180, 2018).