The primary research interests in Dr. Lu’s laboratory focus on four scientific areas: 1. Molecular genetics of renal tract development and birth defects in the kidney and urinary tract; 2. Biological functions and disease mechanisms of renal tract birth defect genes and their roles after birth in common kidney disease; 3. SLIT-ROBO and ZEB signaling in kidney development and disease; 4. Discover and develop novel drug targets and therapeutics for patients with kidney disease.

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 (MCDK), renal cystic disease, hydronephrosis), and ureteric anomalies (e.g. vesicoureteral reflux (VUR), reflux nephropathy, and 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 among the 0 to 12-year age group. CAKUT is also the leading cause of chronic kidney disease and renal failure in children and a major risk factor for kidney failure in adults (Ref 3). Despite high incidence of CAKUT in children and adults with chronic kidney disease and renal failure, the genetic and molecular bases of CAKUT remain largely unclear.

Dr. Lu’s translational research program has adopted combined human and mouse molecular genetics approaches to identify a number of developmental genes to the study of kidney and urinary tract development and pathogenesis of CAKUT and chronic kidney disease. 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 these critical genes (reverse genetics) (Ref 2). Thereafter, molecular identification and analysis of candidate 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 candidate genes in human and mouse. Meanwhile, knockout and transgenic mouse models of candidate genes will be studied to elucidate more fully their roles in kidney and urinary tract development and disease (Ref 5-7). Once these candidate genes (e.g. SLIT2, ROBO2, ZEB2) have been identified, a multidisciplinary 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 chronic kidney disease (Ref 5-7). This multidisciplinary approach includes the use of biomedical research technologies in human and mouse genetics, developmental biology, protein biochemistry, molecular biology, pathology, pharmacology, and drug target discovery. The goal is to provide new knowledge of disease mechanisms underlying developmental antecedents of kidney and urinary tract disorders, which will lead to discoveries of novel drug targets and therapeutics for patients with common kidney diseases (Ref 7) (https://www.eurekalert.org/pub_releases/2016-11/bumc-rip_1111516.php).

Current research activities in Dr. Lu’s lab include (1) Role of SLIT2-ROBO2 and ZEB2 signaling in renal tract development and disease, podocyte biology and injury, pericyte biology and renal fibrosis; (2) Discovery of novel causative and susceptibility genes (e.g. ROBO2, SLIT2, SRGAP1, ZEB2) for renal tract birth defects in children with chronic kidney disease; (3) Identify novel drug targets and therapeutics for patients with chronic kidney disease. 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)


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 in biomedical research and education; (3) to contribute positively to scientific, medical and biomedical community, and society at large.
Core values: curiosity & innovation, diversity & collaboration, 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, 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.

Tou S. Thao (MS in Medical Sciences Program, Graduate Medical Sciences, Boston University School of Medicine), Graduate student, 617-414-2238, tthao@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 (https://open.bu.edu/handle/2144/13984).

Anna Pisarek-Horowitz (PhD, Graduate Program in Molecular Translational Medicine, Graduate Medical Sciences, Boston University School of Medicine). Functional characterization of the SLIT2-ROBO2 signaling pathway in the podocyte (https://open.bu.edu/handle/2144/13990).

Postdoc position and thesis project for graduate students are available. For inquiries regarding these positions, please contact Dr. Lu at wlu@bu.edu