Colleagues: Recently Tenured

REBECCA J. BROWN, M.D., NIDDK

Senior Investigator, Diabetes, Endocrinology, & Obesity Branch, NIDDK

Education: Rice University, Houston (B.A. in chemistry); Mayo Clinic Alix School of Medicine (formerly Mayo Medical School), Rochester, Minnesota (M.D. in medicine); Duke University, Durham, North Carolina (M.S. in health science)

Training: Pediatric resident, University Hospitals Rainbow Babies and Children’s, Cleveland (2002–2005); pediatric endocrinology fellow, NICHD (2005–2008)

Came to NIH: In 2005 as a clinical fellow, NICHD; in 2008 became a senior fellow, NIDDK; in 2012 became an assistant clinical investigator; and in 2015 became a Lasker Clinical Research Scholar, NIDDK

Outside interests: Hiking with my husband and 9-year-old daughter; gardening; reading

Website: https://irp.nih.gov/pi/rebecca-brown

Research interests: The goal of my research program is to understand mechanisms regulating energy metabolism in humans. To accomplish this, I study patients with rare disorders of severe insulin resistance as models to understand perturbations in pathways regulating energy metabolism. I apply what I learn about pathophysiology to develop therapies for these rare and life-threatening diseases and use what I learn from rare diseases to elucidate drug targets for more common disorders of insulin resistance, such as obesity and type 2 diabetes. I study patients with lipodystrophy, characterized by deficiency of body fat; genetic variants of the insulin receptor gene; and autoantibodies to the insulin receptor. These patients, due to extreme phenotypes and clear etiologies, serve as models to understand pathways causing insulin resistance and metabolic syndrome (PMID: 32191645).

One focus of my lab is understanding clinical effects and mechanisms of action of the adipokine leptin. Patients with lipodystrophy are deficient in leptin because they lack adipocytes. We found that leptin replacement in patients with lipodystrophy dramatically improves metabolic disease, which led to FDA approval of recombinant leptin (PMID: 29644599). We also have elucidated multiple mechanisms by which leptin improves metabolic disease (PMID: 29723161; PMID: 33890058).

Future directions: Going forward, my lab seeks to understand mechanisms leading to inadequate triglyceride storage in adipocytes in both patients with lipodystrophy and those with obesity, and we are exploring therapies to enhance adipocyte function (PMID: 36195542). We are also engaged in exciting collaborations aimed at understanding how insulin resistance leads to cardiovascular disease in humans.

ERIC CALVO, PH.D., NIAID

Senior Investigator, Molecular Entomology Section, Laboratory of Malaria and Vector Research, NIAID

Education: University of Havana, Cuba (B.Sc. in biochemistry); Institute of Biomedical Sciences, University of Sao Paulo, Brazil (Ph.D. in parasitology)

Training: IRTA postdoctoral fellow, NIAID (2004–2008)

Before coming to NIH: Staff fellow, Center for Drug Evaluation and Research, FDA, Bethesda, Maryland

Came to NIH: In June 2010 as a staff scientist, NIAID; in 2018 became an Earl Stadtman Investigator and scholar in the NIH Distinguished Scholars Program

Outside interests: Cooking Cuban food; travel

Website: https://irp.nih.gov/pi/eric-calvo

Research interests: I am a vector biologist who is interested in understanding the role of salivary secretions from disease vectors. My laboratory characterizes the functions of salivary proteins from blood-feeding arthropods to understand how they mediate pathogen transmission. This information is synthesized into an integrated model of the vector blood-feeding process and provides new insights into how these processes affect disease transmission and host immunity (PMID: 37469515). To accomplish these aims, we use a combination of bioinformatic analyses, protein chemistry, vascular and structural biology, assay development, and mosquito gene editing based on the CRISPR-Cas9 system. Our research has significantly enhanced our understanding of biologically active salivary proteins from blood-feeding arthropods, including mosquitoes (Culicidae species), sandflies (various genera), and black flies (Simuliidae species; PMID: 37909749; PMID: 35417706). My program has also provided new information on transcriptomics and proteomics of the salivary glands in several major vectors. This work will aid in the identification of salivary proteins that affect virus transmission, in the discovery of immunological markers of vector exposure, and in the identification of pharmacologically active salivary proteins of disease vectors (PMID: 38188518).

Future directions: The functions of most salivary proteins from disease vectors and their effects on blood feeding and disease transmission remain elusive. Approximately 40-50% of these proteins remain to be structurally and functionally characterized. We intend to expand the functional annotation and characterization of salivary proteins for the major insect vectors including mosquitoes, sand flies, and blackflies. Continued technical improvements in the drug discovery field are likely to uncover many new therapeutic leads from salivary secretions.

CHENGKAI DAI, PH.D., NCI

Senior Investigator, Proteomic Instability of Cancer Section, Mouse Cancer Genetics Program, Center for Cancer Research, NCI

Education: Tianjin Medical University, Tianjin, P.R. China (B.M. in clinical medicine, M.S. in pathophysiology); University of Texas, Graduate School of Biomedical Sciences, Houston (Ph.D. in genes and development)

Training: Postdoctoral fellow, Whitehead Institute for Biomedical Research, Cambridge, Massachusetts (2003–2008)

Before coming to NIH: Associate professor, The Jackson Laboratory, Bar Harbor, Maine

Came to NIH: In 2016 as an Earl Stadtman Investigator, NCI

Outside interests: Traveling; reading

Website: https://irp.nih.gov/pi/chengkai-dai

Research interests: 

My research focuses on elucidating how proteomic stability enables oncogenesis. We previously revealed that heat shock factor 1 (HSF1), the master regulator of the cytoprotective heat shock or proteotoxic stress response (HSR/PSR), is a powerful pro-oncogenic factor. Subsequently, we discovered that MEK oncoprotein activates HSF1 via Ser326 phosphorylation to repress tumor-suppressive amyloidogenesis (PMID: 25679764). Furthermore, we found that AKT oncoprotein also activates HSF1 via Ser230 phosphorylation (PMID: 33177089). Hyperactive PI3K/AKT signaling drives tissue overgrowth, accompanied by amyloidogenesis. Uncontrolled protein synthesis underlies this amyloidogenesis. However, HSF1 prevents amyloid-induced apoptosis by neutralizing soluble amyloid oligomers to protect the mitochondrial chaperone HSP60. Our findings suggest amyloidogenesis as a checkpoint mechanism to constrain uncontrolled growth and safeguard tissue homeostasis.

Another focus of my research is to delineate the molecular regulations of HSF1. Contrary to numerous activators, we identified that AMP-activated kinase (AMPK) inactivates HSF1 through Ser121 phosphorylation (PMID: 25425574). Accordingly, the antidiabetic drug metformin suppresses HSF1 via AMPK activation, thereby provoking proteomic instability and impeding in vivo tumor growth. Subsequently, we discovered that HSF1, as a substrate, suppresses AMPK reciprocally by inducing conformational switch of AMPK (PMID: 31561952). This transcription-independent action, importantly, controls lipid metabolism and promotes tumor growth.

Moreover, we uncovered an unexpected role of HSF1 in protein quantity control. By sequestering JNK, HSF1 enables robust mTORC1 signaling and protein translation, thereby sustaining growth (PMID: 27043084). Our recent studies also elucidated a noncanonical transcriptional action of HSF1. Independently of its DNA binding, HSF1 can potentiate the c-MYC-mediated transcription by physically recruiting the histone acetyltransferase GCN5 (PMID: 37224019).

Future directions: Ongoing research includes the elucidation of how the HSF1-mediated HSR/PSR is initiated by proteotoxic stressors, discovery of novel proteostatic mechanisms, and identification of tumor-associated amyloids.

MITCHELL J. MACHIELA, SC.D., NCI

Senior Investigator, Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics (DCEG), NCI

Education: Calvin University, Grand Rapids, Michigan (B.S. in biology); University of Michigan, Ann Arbor, Michigan (MPH in epidemiology); Harvard T.H. Chan School of Public Health, Boston (Sc.D. in epidemiology)

Training: Cancer Research Training Award Fellowship, NCI, Rockville, Maryland (2012–2017)

Came to NIH: In 2012 as a postdoctoral fellow, NCI

Outside interests: Enjoying the outdoors

Website: https://irp.nih.gov/pi/mitchell-machiela 

Research interests: My research is focused on understanding how inherited (germline) variation and acquired (somatic) mutations individually and jointly affect cancer risk. I lead studies of genetic mosaicism to investigate the causes of acquired mosaic chromosomal alterations and their impact on cancer risk. My research uses existing genotype data from DCEG studies and merged international consortia to enable well-powered investigations. I have characterized the frequency and distribution of mosaic chromosomal alterations in existing genotyped populations of blood and buccal DNA (PMID: 25748358), discovered germline contributors to genetic mosaicism (PMID: 27064253; PMID: 38867047), and identified associations between cancer and infectious disease risk, including severe COVID-19 infections (PMID: 38867047).

I also perform genome-wide association studies (GWAS) on pediatric and adult malignancies and have developed the GWAS Explorer as a platform to examine, visualize, and share GWAS summary statistics across several traits. Pediatric cancers like Ewing sarcoma (ES) provide a unique opportunity to study a homogenous tumor with a potentially larger genetic contribution to risk. I lead GWAS on ES to identify susceptibility regions and elucidate the underlying genetic architecture of ES (PMID: 30093639). Findings from ES GWAS have led to regional sequencing studies detailing germline-somatic interactions with ES fusion oncoproteins (PMID: 36787739). I also develop web-based tools including LDlink and AuthorArranger.

Future directions: Most current investigations of genetic mosaicism use cross-sectional data. I am currently working with the NCI’s Prostate, Lung, Colorectal and Ovarian study to examine the clonal dynamics of genetic mosaicism in a large longitudinal series of blood samples. Additionally, I am expanding genetic mosaicism studies to Sub-Saharan African populations to study potential effects of endemic malarial infections on the frequency and genomic distribution.

D. REBECCA PREVOTS, PH.D., NIAID

Senior Investigator, Epidemiology and Population Studies Section, NIAID

Education: Barnard College, Columbia University, New York (B.A. in biology); University of Michigan, Ann Arbor, Michigan (Ph.D and MPH in epidemiology)

Training: Epidemic intelligence service officer, CDC, Atlanta (1991–1993)

Before coming to NIH: Epidemiologist, National Immunization Program (1991–1993 and 1996–2003) and Division of HIV/AIDS Prevention, CDC (1993–1996); Epidemiologist and Technical Advisor, Immunization Program, Pan American Health Organization, Brasilia, Brazil (2000–2002); Public Health Advisor, New York City Department of Health, AIDS Surveillance and Epidemiology Unit (1985–1986)

Came to NIH: In 2003 as epidemiologist, Office of Global Research, NIAID

Outside interests: Biking; dancing (salsa, samba, merengue, contra, and swing)

Website: https://irp.nih.gov/pi/rebecca-prevots

Research interests: I am an infectious disease epidemiologist who joined NIAID with the mission of creating an epidemiology group to enhance the capacity for population-based and clinical research. My lab has focused on the epidemiology of nontuberculous mycobacterial pulmonary disease (NTM PD). We seek to integrate data on environmental factors and host factors and apply multivariable and geospatial analytic techniques to further the understanding of risk factors for NTM PD.

We are pursuing several avenues of research. First, we have leveraged a range of external data sources to establish the burden and trends for NTM disease in the United States (PMID: 37488500; PMID: 38448840; PMID: 32818422; PMID: 35876462). Second, by associating disease data with climate data, we have identified environmental predictors of disease. As part of this work, we have found that selected trace metals in water increase the risk of NTM PD (PMID: 37840858; PMID: 36249270). These findings have informed clinical and experimental studies that are underway, including a clinical study looking at trace metal concentrations in patients at high risk of NTM PD. Finally, we analyze data from NIH clinical cohorts at risk of NTM to elucidate determinants of disease progression (PMID: 35062891).

Future directions: We are studying the effects of climate change on the increasing incidence of NTM PD and plan to use identified climate factors and trends to forecast future disease burden. Separately, we are conducting a GWAS study using genotyped data from more than 100,000 participants in the Kaiser Permanente Research Biobank to better understand host susceptibility.

[COMPILED BY TAYLOR FARLEY, NIAID]