Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation.

My research is focused on defining the molecular underpinnings of podocyte injury and dysfunction in nephrotic syndrome (NS) with a primary focus on focal segmental glomerulosclerosis (FSGS). FSGS is the most common primary glomerular disease that causes end-stage kidney disease in the US and is caused by injury or loss of glomerular visceral epithelial cells (i.e. podocytes). My scientific contributions in the field include the identification of a novel heterozygous missense mutation in Wilms’ Tumor 1 (WT1) that caused non-syndromic familial FSGS (1), the identification of a dominant negative effect of the LIM Homeobox Transcription Factor 1ß R246Q mutation on expression of WT1 (-KTS) isoforms that contributes to the renal-specific phenotype associated with Nail Patella-like Renal Disease (2), and the identification of impaired autophagy and ER stress pathway activation as the cause of podocyte dysfunction and apoptosis induced by the human FSGS-causing ANLN R431C mutation (3). The goal of my research program is to translate novel discoveries in renal genetics into rational therapies and diagnostic tools for patients with NS.

My interests are in the diagnosis and treatment of secondary and inflammatory renal diseases, hypertension and general nephrology. I have been involved specifically in the treatment of childhood hypertension, infections, glomerulonephritis, and secondary disease related to sickle cell anemia, and systemic lupus erythematosus. My previous basic training is in the area of complement mediated injury, immune cell aberrancies, and transplant rejection.

Dr. Foreman's research interests center on participating in multicenter clinical trials investigating new treatments for hypertension and renal disease.

Clinical areas of interest are chronic renal failure, dialysis, transplantation, hypertension, glomerulonephritis, nephrotic syndrome, urinary tract infections, congenital genitourinary anomalies, lupus nephritis,

A major focus of both my clinical practice and investigative work is the diagnosis and treatment of disorders affecting solid-organ transplant recipients, particularly infectious complications. For the past 15 years, I have served as the primary pathologist for one of the largest lung transplant programs in the world; in the process contributing to over 20 peer-reviewed publications on complications of lung transplantation, including infections, gastroesophageal reflux, tumors, and antibody-mediated rejection; and writing a major book chapter on the subject (Howell DN and Palmer SM, Pathology of the Lung Transplant. 2006. In: Lynch JP, Ross D, eds. Lung and Heart-Lung Transplantation. Marcel Dekker, Inc., New York, pp. 683-722). I have also been the primary pathologist for Duke's renal and liver transplant programs, authoring or co-authoring a wide variety of journal articles and a book chapter in these areas (e.g., Plumb et al., Transplantation 2006;82:1224-1224; Snyder et al., Am. J. Respir. Crit. Care Med. 2010;181:1391-1396).

A second major area of interest is the pathogenesis of renal glomerular diseases. In collaboration with members of the Division of Nephrology at Duke, I have helped assemble and characterize a large registry of patients with familial focal segmental glomerulosclerosis (FFSGS)(Conlon et al., Kidney Int. 1999;56:1863-1871). Analysis of one of the families in this registry led to the discovery at Duke, in the laboratory of Dr. Michelle Winn, of mutations in the TRPC6 cation channel as a cause of FFSGS (Winn et al., Genomics 1999;58:113-120; Winn et al., Science 2005;308:1801-1804). We are continuing to collect data on additional families with focal segmental glomerulosclerosis. In addition, I have served as principle consultative pathologist for several investigators working in animal models of renal disease and transplantation (e.g., Crowley et al., Hypertension 2010;55:99-108).

Finally, I have devoted considerable time and energy to applications of correlative microscopy to diagnostic pathology, with particular emphasis electron microscopy. I am currently President of the Society for Ultrastructural Pathology, an international organization that promotes the use of ultrastructural examination in both diagnostic pathology and clinical and basic research. Much of my published work in this area involves the role of electron microscopy in the diagnosis of renal diseases (e.g., Howell et al., Ultrastruct. Pathol. 2003;17:295-312; Pavlisko and Howell, Ultrastruct. Pathol., in press), but I have also written extensively, with my colleague Dr. Sara Miller, on the ultrastructural diagnosis of infectious disorders, contributing, among other things, to the first description of a new polyomavirus-induced skin disorder, trichodysplasia spinulosa (Haycox et al., J. Investig. Dermatol. Symp. Proc. 1999;4:268-271).