Weining Lu MD

Biography

Dr. Lu is a Principal Investigator and Associate Professor of Medicine, Pathology, and Laboratory Medicine at Boston University and Boston Medical Center. He is also the Primary Mentor for medical students, graduate students, undergraduate students, fellows, and postdocs in the Nephrology Section Department of Medicine. Dr. Lu’s laboratory focuses on basic and translational research in 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 significant scientific contributions in the field of nephrology and genetics include: (1) discovering ROBO2 as one of the causative genes for CAKUT and VUR (OMIM 610878), (2) identifying SLIT2/ROBO2 signaling as a novel drug target for proteinuric kidney diseases, which negatively regulates nephrin signaling, nonmuscle myosin IIA signaling and podocyte adhesions in podocyte biology and injury, (3) creating the first animal model for autosomal dominant polycystic kidney disease (PKD1), and (4) discovering ZEB2 as one of the causative genes for glomerulocystic kidney disease and its essential role in kidney stromal progenitor cell differentiation and renal fibrosis. In recognition 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/). Dr. Lu is a fellow of the American Society of Nephrology (ASN) and the International Society of Nephrology (ISN). He is also a member of the NIH grant review study sections of various grant mechanisms, including R01, R21, R03, F32, RC1, RC2, RC4, R13, R15, U01, UH2, UH3, U24, U54, P01, P20, and P50. Dr. Lu is currently an Academic Editor of the scientific journal PLOS ONE.

RESEARCH PROGRAM:

The primary research interests of Dr. Lu’s laboratory focus on basic and translational research in 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 congenital disability 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) Discovery and development of novel drug targets and therapeutics for patients with chronic kidney diseases.

Congenital anomalies of the kidney and urinary tract (CAKUT) is a complex congenital disability 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 also the leading cause of chronic kidney disease and kidney failure in children and young adults under 40 (Ref 3).

Dr. Lu’s basic and translational research program has adopted combined human and mouse molecular genetics approaches to identify developmental genes important in kidney and urinary tract development and pathogenesis of CAKUT. The first human molecular genetics approach is to study patients with CAKUT and apparent genetic defects using gene mutations, genomic imbalances, and chromosomal rearrangements as signposts to identify disease-causal genes (reverse genetics) (Ref 2). After that, molecular identification and analysis of disease genes and mutation studies in affected patients 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 models. Concurrently, the knockout and transgenic mouse models of human disease genes will be generated and examined to recapitulate the human disease phenotype. Once these disease genes (e.g., ROBO2, SLIT2, ZEB2) are identified, and animal models are created, 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 5-9). The multidisciplinary research approach includes pre-clinical animal models, patient samples, and biomarker studies using different new biomedical technology and research techniques in molecular genetics, developmental biology, protein biochemistry, molecular biology, pathology, and pharmacology. Dr. Lu’s basic and translational research program connects the bench and bedside. It has generated new knowledge of disease mechanisms of CAKUT and kidney disease after birth, which facilitates the discovery of novel drug targets and therapeutics for patients with chronic kidney disease (Ref 7-10) (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) the development of novel therapeutics for patients with proteinuric kidney diseases, (2) molecular mechanisms of SLIT/ROBO and ZEB signaling in podocyte biology/injury and kidney fibrosis, and (3) pathogenesis of VUR and CAKUT and identification of novel disease genes causing CAKUT and VUR in patients. Dr. Lu’s research program is supported by grants from the government (e.g., NIH), foundations (e.g., NKF, MOD), and industry (e.g., Pfizer).

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). 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).
(6) Kumar S, Fan X, Rasouly HM, et al. ZEB2 controls kidney stromal progenitor differentiation and inhibits abnormal myofibroblast expansion and kidney fibrosis. JCI Insight 2023, Jan10;(8)1:e158418. PMID: 36445780. https://insight.jci.org/articles/view/158418
(7) 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).
(8) 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).
(9) 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).
(10) Beck LH, Berasi SP, J. Copley B, Gorman D, Levy DI, Lim CN, Henderson JM, Salant DJ, Lu W. PODO: Trial Design: Phase 2 Study of PF-06730512 in Focal Segmental Glomerulosclerosis. Kidney Int Rep 2021; 6(6):1629-1633. PMID: 34169203. DOI: https://doi.org/10.1016/j.ekir.2021.03.892

VISION STATEMENT of Dr. Lu’s laboratory on scientific research and medical 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 the medical and biomedical innovation ecosystem and society at large.
CORE VALUES: Curiosity, Innovation, Diversity, Equity, Inclusion, Accessibility, Hard work, Perseverance, Honesty, Fair play, Courage, Integrity.

CURRENT LAB MEMBERS:

Xueping Fan (PhD, McGill University), Research Scientist and Assistant Professor, 617-414-1772, xpfan@bu.edu.

Sudhir Kumar (DVM, PhD, Ludwig Maximilians University Munich), Research Scientist and Assistant Professor, 617-638-7353, kumars@bu.edu.

Aneesha Pydi (Boston University 7 Year Combined Liberal Arts / Medical Education Program). Research project: “Differential expression of SLIT2N and SLIT2C in adult mouse kidney glomeruli”. Current BU MD medical student, aneeshap@bu.edu

Yuqiao Jiang (BA in Biochemistry & Molecular Biology (BMB)/MA in Biotechnology Program, Boston University College of Arts and Sciences). Currently taking the BMB Undergraduate Laboratory Research Project in Lu Lab titled “Transdermal measurement of glomerular filtration rate in mouse kidney disease models” (Course CAS BB340: Junior Research in BMB, 2 academic credits), yqjiang@bu.edu

Emily Zaltz (Health Science Major, Boston University Sargent College of Health and Rehabilitation Sciences), Undergraduate pre-medical student, BU Undergraduate Research Opportunities Program (UROP), ezaltz@bu.edu

Jessica Siu (Biology Major, Boston University College of Arts & Sciences), Undergraduate pre-dental student, BU Undergraduate Research Opportunities Program (UROP). Current BU Dental Medicine Student, jksiu88@bu.edu

Aksel Laudon (Biomedical Engineering Major, Boston University College of Engineering), BS/MD student, Modular Medical/Dental Integrated Curriculum (MMEDIC) early acceptance program to BU School of Medicine MD program. Competed a BU Biomedical Engineering Senior Project in Lu Lab titled “Digital Biopsy for Glomerular Ultrastructural Measurement in Transmission EM Images” (Course: ENG BE465, 2 academic credits, and ENG BE466, 4 academic credits). Current BU Medical Student, alaudon@bu.edu

GRADUATED FORMER PHD STUDENTS:

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”.

GRADUATED FORMER MS STUDENTS:

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)”. Medical Student at the University of Minnesota Medical School. Current PGY1 Emergency Medicine Resident Physician.

Biomedical research projects for students and postdocs are available. For inquiries regarding these research opportunities, please contact Dr. Lu at wlu@bu.edu