The Falk Labs
Dr. Falk's research probes questions focused on immune mediated kidney diseases, especially glomerulonephritis. His clinical and basic science interests include both ANCA glomerulonephritis and small vessel vasculitis (SVV). A central objective of Falk's research is elucidating the causes of ANCA necrotizing and crescentic glomerulonephritis. Unraveling the cause of this disease requires considering a number of factors involved in the devolpment of ANCA glomerulonephritis. Falk conceptualizes this process as opening the vasculitis lock with a key that has a number of "ridges and valleys" analogous to those factors that contribute to the development of this autoimmune disease. He participates in a research group that, in a large study over the last four years has revealed a number of avenues of investigation and new approaches to ongoing questions that pertain not only to ANCA glomerulonephritis, but to the general fields of autoimmunity, inflammation and basic neutrophil and monocyte biology.
Donna Bunch, PhD Lab
The immune system protects us from infection. Some of the key players in our immune system are special white blood cells called B cells. During an immune response to an invading pathogen, B cells are activated and develop into plasma cells that secrete antibodies specific for that pathogen. Unfortunately, sometimes the immune system can turn on its owner. In autoimmune disease, B cells have escaped the regulation that normally keeps them from making antibodies to things that are part of our bodies (self antigens). Dr. Bunch’s research is focused on understanding how self-reactive B cells are normally regulated to prevent the production of autoantibodies and how tolerance to self is lost in autoimmunity. Specifically, she investigates the generation and regulation of anti-neutrophil cytoplasmic autoantibodies (ANCA) that cause an autoimmune disease that affects the kidneys, ANCA glomerulonephritis.
Dr. Bunch and her co-workers recently identified several immunodominant regions of myeloperoxidase, one of the self-antigens targeted by ANCA, using sera from 14 patients with ANCA glomerulonephritis. Employing a transgenic mouse model, she has determined that B cells reactive with myeloperoxidase are regulated by deletion and diversion to B-1 B cells and thus prevented from developing into antibody-producing cells. Current research in the lab aims to investigate on a cellular level how regulatory mechanisms are circumvented to allow production of pathogenic antibodies. Dr. Bunch and her co-workers study B cells found in the blood of patients with ANCA vasculitis and have identified subpopulations of B cells that differ in patients with active disease compared to patients in remission and healthy controls. It is our hope that by working together with patients and physicians, we can understand ANCA vasculitis better and, hopefully, identify better ways to treat people with this autoimmune disease.
Melanie Joy, PharmD, PhD Lab
Medications taken by patients are handled in various ways by the body. These medications are usually metabolized to a less or inactive moiety that is subsequently eliminated by the kidneys or they are simply eliminated as unchanged drug through the kidneys. However, there are some drugs, including cyclophosphamide that must first be metabolized to an active drug moiety to exert a pharmacological response. The efficiency of drug metabolism can be different in individual patients and this can lead to differences in risks for side events and treatment successes. Medications are transported into and out of cells by proteins on or in the cell membrane. The efficiency of uptake relative to efflux can have implications for treatment effectiveness and toxicity. Various patient and clinical factors can modify metabolism and transport and these include: 1) level of kidney function, 2) type of kidney disease, 3) gender, race, age, and 4) variations in genetic makeup of the genes that encode for the metabolizing enzymes and transporters.
Dr. Joy's research focuses on the role of drug metabolism and transport on pharmacokinetics and pharmacodynamics in various forms of kidney diseases. Dr. Joy has recently investigated the metabolism and transport of drugs used to treat the glomerular diseases ANCA vasculitis, lupus nephritis, and FSGS. Dr. Joy and her collaborators recently demonstrated that patients with glomerular diseases handle drugs differently than patients with kidney diseases of other etiologies. For patients with glomerular diseases it appears that lower drug exposures secondary to enhanced clearances are demonstrated when kidney function is less compromised, e.g. CKD stages 1-3. For patients with later stages of kidney diseases, e.g. stages 4 and 5, however, the role of diminished kidney function on enhancing drug exposures needs to be factored as well. Patients with proteinuria also have increased clearance of therapeutic antibody molecules. Dr. Joy is currently investigating this later research finding in the context of treatment efficacy. The overall goal of Dr. Joy’s current research is to identify enhanced treatment approaches to patients with kidney diseases.
Other areas of study within Dr. Joy’s lab include kidney targeted drug delivery treatment strategies and innovative strategies to reduce the phosphate burden of patients with end stage kidney disease.
Gloria Preston, PhD Lab
Immune cells can mistake your body's own cells as invaders and attack them. This "friendly fire" can affect almost any part of the body. It can sometimes affect many parts of the body at once. This is called autoimmunity (meaning self-immunity). For most autoimmune disorders, a characteristic group of autoantibodies arise. Persistence of these autoantibodies can cause pathological conditions that damage or erode tissues. Dr. Preston's research interests address fundamental genetic and biochemical questions related to an autoimmune disease that affects the kidneys - ANCA glomerulonephritis. Recent discoveries made by Dr. Preston and her coworkers have led to the formulation of a novel theory that delineates potential "triggers" that lead to autoantibody production.
Ongoing research is aimed at dissecting the numerous components that lead to overt ANCA disease. These involve studies of patient-donated samples of leukocytes and serum proteins. Also under investigation is whether specific genes and things in the environment - such as bacteria - are involved. The ultimate goal of this research program is to aid in the understanding ANCA disease - and autoimmune disease in general - with the hope that it will lead to the development of effective and specific therapies.
