Dr. Lu has a long-standing interest and record of accomplishment in the field of nephrology and genetics, including kidney development, congenital anomalies of the kidney and urinary tract (CAKUT), vesicoureteral reflux (VUR), podocyte biology and injury, ROBO/SLIT signaling, and chronic kidney disease. His major scientific contributions in the field include: (1) Discover ROBO2 as one of causative genes for CAKUT and VUR. (2) Identify SLIT/ROBO signaling as a novel drug target for chronic kidney diseases and the first signaling pathway that negatively regulates nephrin signaling, non-muscle myosin IIA signaling and podocyte adhesions in podocyte biology and injury. (3) Create the first animal model for autosomal dominant polycystic kidney disease (PKD1). (4) Discover ZEB2 as one of causative genes for glomerulocystic kidney disease and renal fibrosis. Because of his seminal contribution to the development of a potential new drug for chronic kidney disease in collaboration with Pfizer, Dr. Lu was named the 2019 Boston University Innovator of the Year, an award bestowed annually on a faculty member who “translates his/her world-class research into inventions and innovations that benefit humankind” (https://www.bu.edu/articles/2019/weining-lu-kidney-researcher-innovator-of-the-year/).
RESEARCH PROGRAM:
The primary research interests in Dr. Lu’s laboratory focus on four scientific areas: 1) Molecular genetics of the kidney and urinary tract development and congenital anomalies of the kidney and urinary tract (CAKUT). 2) Biological function and disease mechanism of kidney and urinary tract birth defect genes and their roles after birth in chronic kidney diseases. 3) SLIT/ROBO and ZEB signaling in kidney and urinary tract development and disease. 4) Discover and develop novel drug targets and therapeutics for patients with chronic kidney diseases.
Congenital anomalies of the kidney and urinary tract (CAKUT) is a complex birth defect with a diverse phenotypic spectrum, including kidney anomalies (e.g. renal agenesis, multicystic dysplastic kidney, hydronephrosis), and ureteric anomalies (e.g. vesicoureteral reflux, obstructive uropathy) (Ref 1, 2). CAKUT is a genetically heterogeneous disorder with an incidence of 1 in 100 infants and accounts for up to 50-60% of the diagnoses underlying chronic kidney disease in children. CAKUT is also the leading cause and a major risk factor for kidney failure in children and adults (Ref 3).
Dr. Lu’s translational research program has adopted combined human and mouse molecular genetics approaches to identify a number of developmental genes that are important in kidney and urinary tract development and pathogenesis of CAKUT. The first human molecular genetics approach is to study individuals with CAKUT and apparent genetic defects, with the aim of using gene mutations, genomic imbalances and chromosomal rearrangements as signposts to identify disease causal genes (reverse genetics) (Ref 2). Thereafter, molecular identification and analysis of disease genes as well as mutation studies in affected individuals with a familial pattern of CAKUT will be carried out (forward genetics) (Ref 2, 4). The second approach is to study temporal and spatial expression patterns of disease genes in human and mouse. Meanwhile, the phenotype of knockout and transgenic mouse models of these disease genes will be studied to elucidate more fully their roles in kidney and urinary tract development and disease. Once these disease genes (e.g. ROBO2, SLIT2, ZEB2) are identified, a multidisciplinary research approach will be taken to gain further mechanistic insights in vivo and in vitro on the role of these genes in normal and abnormal developmental processes of the kidney and urinary tract, and on the pathogenesis of CAKUT and kidney injury after birth (Ref 5-8). This multidisciplinary approach includes using biomedical research techniques in molecular genetics, developmental biology, protein biochemistry, molecular biology, pathology, and pharmacology. The goal is to provide new knowledge of biological mechanism that leads to CAKUT and kidney injury after birth, which may lead to the discovery of novel drug targets and therapeutics for patients with chronic kidney disease (Ref 7-8) (https://www.eurekalert.org/pub_releases/2016-11/bumc-rip_1111516.php & https://www.eurekalert.org/pub_releases/2020-05/buso-rsn050420.php).
Current research projects in Dr. Lu’s lab include: (1) Development of novel therapeutics for patients with glomerular kidney disease. (2) Molecular mechanisms of SLIT/ROBO and ZEB signaling in podocyte biology/injury and renal fibrosis. (3) Pathogenesis of VUR and CAKUT and identification of novel causative birth defect genes for CAKUT/VUR in patients. Dr. Lu’s research program is supported by grants from the National Institutes of Health (NIH) and Pfizer Centers for Therapeutic Innovation.
REFERENCES:
(1). Lu W, Bush KT, Nigam SK. Regulation of ureteric bud outgrowth and the consequences of disrupted development. In Kidney Development, Disease, Repair and Regeneration (ed. Little MH), Pages 209-227 (Elsevier, 2016) (http://www.sciencedirect.com/science/article/pii/B9780128001028000187)
(2). Lu W, van Eerde AM, Fan X, et al. Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux. Am J Hum Genet 2007; 80:616-632. PMID: 17357069 (http://www.ncbi.nlm.nih.gov/pubmed/17357069).
(3) Calderon-Margalit R, Golan E, Twig G, et al. History of Childhood Kidney Disease and Risk of Adult End-Stage Renal Disease. N Engl J Med 2018; 378(5):4280438. PMID: 29385364 (https://www.ncbi.nlm.nih.gov/pubmed/29385364).
(4) Hwang DY, Kohl S, Fan X, et al. Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 Confer Risk for Congenital Anomalies of the Kidney and Urinary Tract. Hum Genet 2015; 134(8):905-916; PMID: 26026792 (http://www.ncbi.nlm.nih.gov/pubmed/26026792).
(5). Fan X, Li Q, Pisarek-Horowitz A, et al. Inhibitory effects of Robo2 on nephrin: a crosstalk between positive and negative signals regulating podocyte structure. Cell Reports 2012; 2:52-61. PMID: 22840396 (http://www.ncbi.nlm.nih.gov/pubmed/22840396).
(6). Rasouly HM, Kumar S, Chen S, et al. Loss of Zeb2 in mesenchyme-derived nephrons causes primary glomerulocystic kidney disease. Kidney Int 2016; Aug 30. PMID: 27591083 (http://www.ncbi.nlm.nih.gov/pubmed/27591083).
(7) Fan X, Yang H, Kumar S, et al. SLIT2/ROBO2 signaling pathway inhibits nonmuscle myosin IIA activity and destabilizes kidney podocyte adhesion. JCI Insight 2016, Nov 17; 1(19):e86934. PMID: 27882344 (https://www.ncbi.nlm.nih.gov/pubmed/27882344)
(8) Pisarek-Horowitz A, Fan X, Kumar S, et al. Loss of Roundabout Guidance Receptor 2 (Robo2) in Podocytes Protects Adult Mice from Glomerular Injury by Maintaining Podocyte Foot Process Structure. American Journal of Pathology, 2020; 190(4):799-816. PMID: 32220420.
(https://ajp.amjpathol.org/article/S0002-9440(20)30024-9/pdf)
VISION STATEMENT of Dr. Lu’s laboratory on science and education: (1) to advance new knowledge, biomedical innovation, and scientific learning; (2) to promote understanding, collaboration, diversity and inclusion in biomedical research and education; (3) to contribute positively to scientific, medical and biomedical community, and society at large.
CORE VALUES: curiosity & innovation, diversity & inclusion, hard work & perseverance, honesty & fair play, courage & integrity.
CURRENT LAB MEMBERS:
Xueping Fan (PhD, McGill University), Instructor in Medicine, 617-414-1772, xpfan@bu.edu.
Sudhir Kumar (DVM, PhD, Ludwig Maximilians University Munich), Postdoc, 617-638-7353, kumars@bu.edu.
Richa Sharma (PhD, SGPGIMS Medical Institute in Lucknow), Postdoc, 617-414-2298, richa26@bu.edu.
Aneesha Pydi (Boston University 7 Year Combined Liberal Arts / Medical Education Program), MD student, aneeshap@bu.edu
Rhianna DelBene (Boston University College of Arts & Sciences), Undergraduate student, BU Undergraduate Research Opportunities Program (UROP). rdelbene@bu.edu
PHD STUDENTS GRADUATED RECENTLY:
Hila Milo Rasouly (PhD, Graduate Program in Genetics and Genomics, Graduate Medical Sciences, Boston University School of Medicine). PhD thesis title: “Discovery and analysis of genes important in kidney development and disease”.
Anna Pisarek-Horowitz (PhD, Graduate Program in Molecular Translational Medicine, Graduate Medical Sciences, Boston University School of Medicine). PhD thesis title: “Functional characterization of the SLIT2-ROBO2 signaling pathway in the podocyte”.
MS STUDENTS GRADUATED RECENTLY:
Tou S. Thao (MS in Medical Sciences Program, Graduate Medical Sciences, Boston University School of Medicine). MS thesis title: “Functional study of ROBO2 missense mutation identified in patients with congenital anomalies of the kidney and urinary tract (CAKUT)”.
Postdoc position and thesis project for students are available. For inquiries regarding these positions, please contact Dr. Lu at wlu@bu.edu