The theme of the laboratory (Program in Membrane Biology, PMB) is to understand how membrane transport vesicles interact with accessory proteins (GTPases, SNAREs, kinases) and with the cytoskeleton (microtubules, actin, and PDZ proteins) to modulate cell function via various membrane transport proteins in physiological and pathophysiological conditions. Experimental models used range from in vitro systems using purified proteins and membrane vesicles (endosomes, Golgi, plasma membrane), to transfected cell cultures, to whole animal models including transgenic mice. All projects are interactive and involve cell biological procedures such as confocal and EM-gold immunocytochemistry, real time confocal and TIRF microscopy. In addition, molecular and biochemical procedures are combined with cell biology to provide a multidisciplinary approach to problem solving. The aim of the research is to understand how physiologically-relevant processes of fluid and electrolyte transport across epithelia are regulated at the cell and molecular levels in kidney, the male reproductive tract and other organ systems.
Grune J, Lewis AJM, Yamazoe M, Hulsmans M, Rohde D, Xiao L, Zhang S, Ott C, Calcagno DM, Zhou Y, Timm K, Shanmuganathan M, Pulous FE, Schloss MJ, Foy BH, Capen D, Vinegoni C, Wojtkiewicz GR, Iwamoto I, Grune T, Brown D, Higgins J, Ferreira VM, Herring N, Channon KM, Neubauer S, Oxford Acute Myocardial Infarction (OxAMI) Study, Sosnovik DE, Milan DJ, Swirski FK, King KR, Aguirre AD, Ellinor PT, Nahrendorf M Neutrophils incite and macrophages avert electrical storm after myocardial infarction. Nat Cardiovasc Res. 2022;1(7):649-664 - PMID: 36034743 - PMCID: PMC9410341 - DOI: 10.1038/s44161-022-00094-w
Schloss MJ, Hulsmans M, Rohde D, Lee IH, Severe N, Foy BH, Pulous FE, Zhang S, Kokkaliaris KD, Frodermann V, Courties G, Yang C, Iwamoto Y, Knudsen AS, McAlpine CS, Yamazoe M, Schmidt SP, Wojtkiewicz GR, Masson GS, Gustafsson K, Capen D, Brown D, Higgins JM, Scadden DT, Libby P, Swirski FK, Naxerova K, Nahrendorf M B lymphocyte-derived acetylcholine limits steady-state and emergency hematopoiesis. Nat Immunol. 2022;23(4):605-618 - PMID: 35352063 - PMCID: PMC8989652 - DOI: 10.1038/s41590-022-01165-7
Zaidman NA, Tomilin VN, Hassanzadeh Khayyat N, Damarla M, Tidmore J, Capen DE, Brown D, Pochynyuk OM, Pluznick JL Adhesion-GPCR Gpr116 (ADGRF5) expression inhibits renal acid secretion. Proc Natl Acad Sci U S A. 2020;117(42):26470-26481 - PMID: 33004624 - PMCID: PMC7584995 - DOI: 10.1073/pnas.2007620117
Mendelsohn AC, Sanmarco LM, Spallanzani RG, Brown D, Quintana FJ, Breton S, Battistone MA From initial segment to cauda: A regional characterization of mouse epididymal CD11c+ mononuclear phagocytes based on immune phenotype and function. 2020;319(6):C997-C1010 - PMID: 32991210 - PMCID: PMC7792679 - DOI: 10.1152/ajpcell.00392.2020
Brown CR, Gupta S, Qin J, Racie T, He G, Lentini S, Malone R, Yu M, Matsuda S, Shulga-Morskaya S, Nair AV, Theile CS, Schmidt K, Shahraz A, Goel V, Parmar RG, Zlatev I, Schlegel MK, Nair JK, Jayaraman M, Manoharan M, Brown D, Maier MA, Jadhav V Investigating the pharmacodynamic durability of GalNAc-siRNA conjugates. Nucleic Acids Res. 2020;48(21):11827-11844 - PMID: 32808038 - PMCID: PMC7708070 - DOI: 10.1093/nar/gkaa670
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Aquaporin (water channel) trafficking
We are dissecting the mechanisms of water channel (aquaporins 1, 2, 4 and 9) trafficking and regulation in epithelial cells from the kidney and male reproductive tract. These channels play a crucial role in maintaining body fluid homeostasis, and the specific functions of diverse organ systems including the eye, ear, brain and reproductive tract.
Vacuolar H+ATPase (proton pump) trafficking and regulation
Specialized proton secreting epithelial cells are involved in acid-base regulation in the kidney and in sperm maturation in the epididymis. We have identified a soluble adenylate cyclase (sAC) as a sensor of extracellular pH and bicarbonate in the epididymis and vas deferens, and are examining the role of this protein in pH sensing by cells in general.
Endocytotic mechanisms in renal tubular cells
Endocytosis of filtered proteins (albumin) is a major function of the renal proximal tubule that is perturbed in disease states, including diabetes. This leads to loss of albumin in the urine. We are using in vitro systems and animal models to explore proximal tubule receptor mediated endocytosis of albumin with the aim of discovering new strategies for treating albuminuria.
pH sensing in endosomes
Endosomes respond to intravesicular acidic pH by recruiting cytosolic coat components that regulate their trafficking. We have recently identified the H+ATPase as an endosomal pH sensor and we are determining its role in coat recruitment and vesicle trafficking in the protein degradative pathway in epithelial cells.
G-protein coupled receptor trafficking and signaling
We are using diverse microscopic (FRET), biochemical, molecular and pharmacological tools to understand how G-protein coupled vasopressin and PTH receptors signal upon ligand binding. These receptors are involved in various critical aspects of fluid and electrolyte balance, mainly via actions on kidney epithelial cells.
Regulation of iron metabolism
This is a complex process that involves many proteins that bind to and transport iron in and out of cells in a highly coordinated manner. Recently, we established a fundamental link between bone morphogenic protein (BMP) signaling and iron metabolism. By studying this complex but important signaling pathway, we hope to shed light on iron dysregulation diseases such as hemochromatosis and anemia of chronic disease.
Dennis Brown, PhD has been elected as a member of Academia Europaea (The Academy of Europe). Academia Europaea is the only Europe-wide academy with individual membership from Council of Europe states and other nations across the world.
Dennis Brown, PhD, Professor of Medicine and Director of the MGH Program in Membrane Biology, part of the Division of Nephrology and the Center for Systems Biology, was elected by a poll of its members as the new President Elect of the American Physiological Society (APS). Established in 1887, the American Physiological Society (APS) was the first U.S. society in the biomedical sciences field. The Society represents more than 11,000 members and publishes 14 peer-reviewed journals with a worldwide readership.
CSB PMB work on high resolution imaging of the kidney using helium ion microscopy (Rice et al., PLoSONE 8(3); e57051, 2013) was featured recently in the annual report from the NIDDK (Recent Advances and Emerging Opportunities) under the heading “A closer look at kidney structure”. (pdf)
Congratulations to Dennis Brown, PhD, who was awarded an Honorary Doctorate of Science by his alma mater, the University of East Anglia, Norwich, UK at a congregation held on Thursday July 18th, 2013. The honor was bestowed in recognition of his contributions to cell biology and physiology. The following week on July 25th, he gave the prestigious Robert Pitts Lecture in Renal Physiology at the International Union of Physiological Sciences meeting in Birmingham, UK
Dennis Brown, PhD received the 2012 Joseph B. Martin Dean’s Award for Leadership in the Advancement of Women at Harvard Medical School and Harvard School of Dental Medicine. This prestigious award is co-sponsored by the Joint Committee on the Status of Women and the Dean of the Faculty of Medicine. It was initiated by Dean Joseph B. Martin in 1998 to recognize Harvard faculty and staff members committed to the recruitment, retention, and advancement of women at Harvard Medical School and Harvard School of Dental Medicine. Over the past 25 years, Dr. Brown recruited and trained over 30 female scientists. While some are currently working with Dennis, others are occupying senior academic positions at institutions around the globe. Congratulations Dennis for a well-deserved award!