Prostate cancer is the most commonly diagnosed malignancy in men in the United States, although our understanding of the molecular basis for this disease remains incomplete. We are interested in characterizing consistent alterations in the structure and expression of the genome of human prostate cancer cells as a means of identifying genes critical in the pathways of prostatic carcinogenesis. We are focusing on somatic genomic alterations occurring in sporadic prostate cancers, as well as germline variations which confer increases in prostate cancer risk. Both genome wide and candidate gene approaches are being pursued, and cancer associated changes in gene expression analyses of normal and malignant prostate cells are being cataloged as a complementary approach in these efforts. It is anticipated that this work will assist in providing more effective methodologies to identify men at high risk for this disease, in general, and in particular, to identify new markers of prognostic and therapeutic significance that could lead to more effective management of this common disease.

Normal and neoplastic cells respond to genome integrity threats in a variety of different ways. Furthermore, the nature of these responses are critical both for cancer pathogenesis and for cancer treatment. DNA damaging agents activate several signal transduction pathways in damaged cells which trigger cell fate decisions such as proliferation, genomic repair, differentiation, and cell death. For normal cells, failure of a DNA damaging agent (i.e., a carcinogen) to activate processes culminating in DNA repair or in cell death might promote neoplastic transformation. For cancer cells, failure of a DNA damaging agent (i.e., an antineoplastic drug) to promote differentiation or cell death might undermine cancer treatment. Our laboratory has discovered the most common known somatic genome alteration in human prostatic carcinoma cells. The DNA lesion, hypermethylation of deoxycytidine nucleotides in the promoter of a carcinogen-defense enzyme gene, appears to result in inactivation of the gene and a resultant increased vulnerability of prostatic cells to carcinogens. Studies underway in the laboratory have been directed at characterizing the genomic abnormality further, and at developing methods to restore expression of epigenetically silenced genes and/or to augment expression of other carcinogen-defense enzymes in prostate cells as prostate cancer prevention strategies. Another major interest pursued in the laboratory is the role of chronic or recurrent inflammation as a cause of prostate cancer. Genetic studies of familial prostate cancer have identified defects in genes regulating host inflammatory responses to infections. A newly described prostate lesion, proliferative inflammatory atrophy (PIA), appears to be an early prostate cancer precursor. Current experimental approaches feature induction of chronic prostate inflammation in laboratory mice and rats, and monitoring the consequences on the development of PIA and prostate cancer.

The focus of the research in the Reddy Laboratory is to begin to understand how the nuclear periphery and other subcompartments contribute to general nuclear architecture and to specific gene regulation. Our research goals can be broken down into three complementary areas of research: understanding how genes are regulated at the nuclear periphery, deciphering how genes are localized (or ""addressed"") to specific nuclear compartments and how these processes are utilized in development and corrupted in disease.

HPTN (HIV Prevention Trials Network) Network Laboratory (NL) is responsible for collecting, testing and reporting results from biological samples; assisting in the development and quality assurance assessment of local laboratory capacity at the Clinical Trials Units (CTUs) participating in HPTN clinical trials (www.hptn.org); and identifying and implementing state-of-the-art assays and technologies to advance the scientific agenda of the Network.

Research in the Mihail Zilbermint Lab focuses on diabetes, adrenal disease and thyroid disease. Recent areas of focus include pseudohypoaldosteronism type 1 related to novel variants of SCNN1B gene, genetic variance in the ARMC5 gene in primary macronodular adrenocortical hyperplasia and hyperaldosteronism due to de novo KCNJ5 mutation.

Research in the Ruth Faden Lab focuses on biomedical ethics and health policy. Our specific areas of interest include justice theory; national and global challenges in learning health care systems, health-system design and priority setting; access global investments benefits in biomedical research; and ethical challenges in biomedical science and women’s health.

Research in the Howard and Georgeanna Seegar Jones Reproductive Endocrinology Lab supports a broad interest in reproductive conditions, but has a particular focus on endometriosis, uterine fibroids, polycystic ovary syndrome (PCOS) and genes causing infertility. PCOS and uterine fibroids are among the most prevalent conditions leading to infertility and diseases in women, but both remain poorly understood. Studying these areas may lead to the development of new treatments or preventative therapies.

The Taverna Laboratory studies histone marks, such as lysine methylation and acetylation, and how they contribute to an epigenetic/histone code that dictates chromatin-templated functions like transcriptional activation and gene silencing. Our lab uses biochemistry and cell biology in a variety of model organisms to explore connections between gene regulation and proteins that write and read histone marks, many of which have clear links to human diseases like leukemia and other cancers. We also investigate links between small RNAs and histone marks involved in gene silencing.

xResearch in the Shyam Biswal Lab focuses on therapeutic resistance of cancer due to a gain-of-function mutation in transcription factor Nrf2. Using patient-derived xenografts in humanized immunocompetent mice and GEM models, we aim to understand the mechanisms of oncogenic cooperation and metabolic adaptation in cancer cells. We’re also investigating the systemic and pulmonary effects of air pollution as well as the health effects of recent tobacco products, such as electronic cigarettes and water pipes.

Our lab is focused on using comprehensive gene expression, methylation and sequencing and metabolomics analysis to identify alterations in breast cancer, and exploiting these for early detection and therapy. Among deferentially expressed genes, our lab has focused on the HOX genes. HOX genes are intimately involved in the development of resistance to both chemotherapy and to agents targeting the estrogen receptor. Our work explores the alternate pathways that are activated by HOX proteins leading to this resistance and novel treatments to overcome resistance in both tissue culture and xenograft models. In addition, epigenetically silenced genes and a metabolic reprogramming in tumors also trigger novel early detection and therapeutic strategies. We are testing the utility of differentiation therapy through reactivating RAR-beta in breast cancer using histone deacetylase inhibitors with great success. Also, we are targeting enzymes involved in gluconeogenesis and glycolysis with small molecule FDA-approved antimetabolites to achieve antitumor effects.