Zhe Han, PhD

Han, Z., Fujioka, M., Su, M., Liu, M., Jaynes, J.B., and Bodmer, R. (2002). Transcriptional integration of competence modulated by mutual repression generates cell-type specificity within the cardiogenic mesoderm. Developmental Biology252(2), 225-240. PMID: 12482712; PMCID: PMC2693947.

Han, Z., Bodmer, R. (2003). Myogenic cells fates are antagonized by Notchonly in asymmetric lineages of the Drosophilaheart, with or without cell division. Development130(13), 3039-3051.PMID: 12756185. 

Han, Z., Li, X., Wu, J. and Olson, E.N. (2004). A myocardin-related transcription factor regulates activity of serum response factor in Drosophila. Proceedings of the National Academy of Sciences101(34), 12567-12572. PMID: 15314239; PMCID: PMC515097.

Han, Z., Olson, E.N. (2005). Hand is a direct target of Tinman and GATA factors during Drosophilacardiogenesis and hematopoiesis. Development132(15): 3525-3536. PMID: 15975941.

Fujioka, M., Wessells, R. J., Han, Z., Liu, J., Fitzgerald, K., Yusibova, G. L., Zamora, M., Ruiz-Lozano, P., Bodmer, R., Jaynes, J. B. (2005). Embryonic even-skipped-Dependent Muscle and Heart Cell Fates Are Required for Normal Adult Activity, Heart Function, and Lifespan. Circulation Research97(11), 1108-1114. PMID: 16239588; PMCID: PMC2726805.

Kwon, C.*, Han, Z.*, Olson, E.N., Srivastava, D. (2005). DrosophilamicroRNA1 regulates Notch signaling during cardiac lineage determination and differentiation. Proceedings of the National Academy of Sciences 102(52), 18987-18991 (*Co-first author). PMID: 16357195; PMCID: PMC1315275.

Han, Z., Yi, P., Li, X., Olson, E.N.(2006). Hand, an evolutionarily conserved bHLH transcription factor required for Drosophilacardiogenesis and hematopoiesis. Development133 (6): 1175-1182.PMID: 16467358.

Yi, P.*, Han, Z.*^,#, Li, X., Olson, E. N^#. (2006). The mevalonate pathway controls heart formation in Drosophila by isoprenylation of Ggamma1. Science313(5791): 1301 – 1303. PMID: 16857902. (*Co-first author and ^#co-corresponding author).(This paper was featured in Editor’s Choice titled “Holding the heart together”, Science Signaling351, p307, 2006)

Liotta, D., Han, J., Elgar, S., Garvey, C., Han, Z., and Taylor, M.V. (2007). The Him gene reveals a balance of inputs controlling muscle differentiation in Drosophila Current Biology. 17(16):1409-1413. PMID: 17702578; PMCID: PMC1955682.

Liu, J., Qian, L., Han, Z., Wu, X, Bodmer, R. (2008). Spatial specificity of mesodermal even-skipped expression relies on multiple repressor sites. Developmental Biology313(2), 876-886. PMID: 18067885;PMCID: PMC2245897.

Elalayli, M., Hall, J. D., Fakhouri, M., Neiswender, H., Ellison, T., Han, Z., Roon, P., LeMosy, E. K. (2008).Palisade is required in the Drosophilaovary for assembly and function of the protective vitelline membrane. Developmental Biology319(2), 359-369. PMID: 18514182; PMCID: PMC2536644.

Yi, P., Johnson A. N., Han, Z., Wu, J., and Olson, E. N. (2008). Heterotrimeric G proteins regulate a noncanonical function of septate junction proteins to maintain cardiac integrity in Drosophila. Developmental Cell, 15(5): 704 – 713. PMID: 19000835; PMCID: PMC2736786.

Chen, Z., Liang, S., Zhao, Y., and Han, Z. (2012). MiR-92b regulates Mef2 levels through a negative feedback circuit during Drosophila muscle development. Development139(19): 3543-3552. Epub Aug. 16, 2012. PMID: 22899845; PMCID: PMC3436111.

Zhang, F., Zhao, Y., and Han, Z. (2013). An in vivofunctional analysis system for renal gene discovery in Drosophilapericardial nephrocytes. Journal of the American Society of Nephrology24(2): 191-197. Epub Jan. 4, 2013. PMID: 23291470; PMCID: PMC3559487. (This paper was featured as “This Month’s Highlights” in JASN: “Drosophila facilitate study of podocytes”, by JASN editors.)

Zhang, F., Zhao, Y., Chao, Y., Muir, K., and Han, Z. (2013). Cubilin and Amnionless mediate protein reabsorption in Drosophila Journal of the American Society of Nephrology24(2): 209-216. Epub Dec. 20, 2012. PMID: 23264686; PMCID: PMC3559489. (This paper was featured in commentary: “The Drosophila nephrocyte: Back on stage”, Na, J. and Cagan, R., Journal of the American Society of Nephrology24, 161-163, 2013.)

Gee, H.Y., Saisawat, P., Ashraf, S., Hurd, T.W., Vega-Warner, V., Fang, H., Beck, B.B., Gribouval, O., Zhou, W., Diaz, K.A., Natarajan, S., Wiggins, R.C., Lovric, S., Chernin, G., Schoeb, D.S., Ovunc, B., Frishberg, Y., Soliman, N.A., Fathy, H.M., Goebel, H., Hoefele, J., Webernn, J.W., Faul, C., Han, Z., Washburn, J., Antignac, C., Levy, S., Otto, E.A., Hildebrandt, F. (2013). ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling. Journal of Clinical Investigation123, 3243 - 3253. PMID: 23867502.

Ashraf S., Gee H. Y., Woerner, S., Vega-Warner, V., Lovric, S., Fang, H., Xie, L., Song, X., Cattran, D.C., Paterson, A., Nitschké, P., Cochat, P., Zhou, W., Airik, R., Allen, S., Otto, E., Kari, J., Böckenhauer, D., Kleta, R., Gok, F., Washburn, J., Wiggins, R.C., Choi, M., Lifton R.P., Levy S., Han, Z.,Salviati L., William, D.S.,Pollak, M., Pei, Y., Antignac, C., Hildebrandt., F. (2013). Exome resequencing reveals ADCK4 mutations as a novel cause of steroidresistant nephrotic syndrome. Journal of Clinical Investigation123(12), 5179-5189. PMID: 24270420; PMCID: PMC3859425

Gee, H.Y., Zhang F., Ashraf, S., Kohl, S., Sadowski C., Vega-Warner, V., Zhou, W., Fang H., Lovric, S., Hoefele, J., Weber, L., Podracka, L., Boor, A., Innis, J., Washburn, J., Salviati L., William, D.S., Levy, S., Otto, E., Han, Z.*, and Hildebrandt, F.* (2015) KANK deficiency leads to defective podocyte function and nephrotic syndrome. Journal of Clinical Investigation125(6), 2375-2384. PMID: 25961457; PMCID: PMC4497755. (*Co-corresponding author).

Fulga T.A., McNeill, E.M., Binari, R., Yelick, J., Blanche, A., Booker, M., Zhao, Y., Bejarano, F., Han, Z.,Lai, E.C., Wall, D.P., Perrimon, N., Van Vactor, D. (2015) A transgenic resource for conditional competitive inhibition of conserved Drosophila microRNAs. Nature Communication.6: 7279, E-published on June 17, 2015). PMID:26081261; PMCID: PMC4471878

Chen, Z. Zhu, J.Y., Fu, Y., Richman, A., and Han, Z.(2016) Wnt4 is required for ostia development in the Drosophila Developmental Biology 413, 188-198. PMID: 26994311; PMCID: PMC4857614.

Patel, M.V., Zhu, J.Y., Jiang, Z., Richman, A., VanBerkumF. and Han, Z.(2016) Gia/Mthl5 is an aorta specific GPCR required for Drosophilaheart tube morphology and normal pericardial cell positioning. Developmental Biology 414, 100-107. PMID: 26994946; PMCID: PMC4875858

Jiang, Z., Li, F., Wan, Y., Han, Z.,Yuan, W., Cao, L., Deng, Y., Peng, X., Chen, F., Fan, X., Liu, X., Dai, G., Wang, Y., Zeng, Q., Shi, Y., Zhou, Z., Chen, Y., Xu, W., Luo, S., Chen, S., Ye, X., Mo, X., Wu, X., and Li, Y. (2016) LASS5 Interacts with SDHB and Synergistically Represses p53 and p21 Activity. Current Molecular Medicine16(6):582-90. PMID: 27280497; PMCID: PMC5280074.

Li, J., Das, J.R., Tang, P., Han, Z.,Jaiswal, J.K., Ray, P.E. (2016) Transmembrane TNF-α Facilitates HIV-1 Infection of Podocytes Cultured from Children with HIV-Associated Nephropathy. Journal of the American Society of Nephrology28(3): 862-875. E-published on Nov. 3, 2016. PMID: 27811066; PMCID: PMC5328167.

Fu, Y., Zhu, J.Y., Richman, A., Zhang, Y., Xie, X., Das, J.R., Li, J., Ray, P.E., and Han, Z. (2017) APOL1-G1 in nephrocytes induces hypertrophy and accelerates cell death. Journal of the American Society of Nephrology 28(4): 1106-1116.E-published on Nov. 18, 2016. PMID: 27864430; PMCID: PMC5373456. (Featured by editorial “Mechanisms of APOL1-associated renal disease”, Nature Review Nephrology13, page 62, 2017.)

Zhu, S., Han, Z.,Luo, Y., Chen, Y., Zeng, Q., Wu, X., and Yuan, W. (2016) Molecular mechanisms of heart failure: insights from Drosophila. Heart Failure Review22(1): 91-98. E-published on Dec. 1, 2016. PMID: 27904993; PMCID: PMC5222906.

Zhu, J.Y., Fu, Y., Nettleton, M., Richman, A., and Han, Z.(2017). High throughput in vivo functional validation of candidate congenital heart disease genes in Drosophila. eLife(E-published on Jan. 20, 2017). PMID: 28084990; PMCID: PMC5300701.

Fu, Y., Zhu, J.Y., Richman, A., Zhao, Z., Zhang, F., Ray, P.E., Han, Z.(2017) A Drosophila model system to assess the function of human monogenic podocyte mutations that cause nephrotic syndrome. Human Molecular Genetics 26(4): 768-780. E-published on Feb. 6, 2017. PMID: 28164240.

Fu, Y., Zhu, J.Y., Zhang, F., Richman, A., Zhao, Z., and Han, Z.(2017) Comprehensive functional analysis of Rab GTPase genes in Drosophila nephrocytes. Cell and Tissue Research368(3): 615-627. E-published on Feb. 8, 2017. PMID: 28180992; PMCID: PMC5429992.

Zhu, J.Y., Heidersbach, A., Kathiriya, I.S., Garay, B.I., Ivey, K.N., Srivastava, D., Han, Z.*,and King, I.N.* (2017) The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA-1. Development144, 866-875. (*Co-corresponding author, E-published on Mar. 1, 2017). PMID: 28246214; PMCID: PMC5374346.

Zhu, J.Y., Fu, Y., Richman, A., and Han, Z*.(2017). Validating candidate congenital heart disease genes in Drosophila.Bio Protocol(E-published on June 20, 2017), Vol 7, Issue 12. PMID: 29276722. (*Corresponding author).

Zhu, J.Y., Fu, Y., Richman, A., Zhao, Z., Ray, P.E., and Han, Z.(2017) A personalized Drosophila model of COQ2 nephropathy rescued by the wild-type human COQ2 allele and dietary Q10 supplementation. Journal of the American Society of Nephrology 28(9): 2607 – 2617. PMID: 28428331; PMCID: PMC5576924. (Featured on the cover of JASN for the September 2017 issue).

Basu, M., Zhu, J.Y., LaHaye, S., Majumdar, U., Jiao, K., Han, Z.*,and Garg, V.* (2017) Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease. JCI Insight2(20), E-published on Oct. 19, 2017. PMID: 29046480. (*Co-corresponding author).

Okamoto, K., Rausch, J.W., Wakashin, H., Fu, Y., Chung, J.Y., Dummer, P.D., Shin, M., Chandra, P., Suzuki, K., Shrivastav, S., Rosenberg, A.Z., Hewitt, S.M., Ray, P., Noiri, E., Grice, S.F., Hoek, M., Han, Z.,Kopp, J.B. (2018) APOL1 risk allele RNA contributes to renal toxicity injury by activating protein kinase R.  Communications Biology1, 188. E-published on Nov. 7, 2018. PMID: 30417125.

Zhao, F., Zhu, J.Y., Richman, A., Fu, Y., Huang, W., Chen, N., Pan, X., Yi, C., Ding, X., Wang, S., Ma, Y., Nie, X., Huang, J., Yang, Y., Yu, Z., and Han, Z*.(2019) Mutations in NUP160are implicated in Steroid-Resistant Nephrotic Syndrome. Journal of the American Society of Nephrology (E-pub on March 25, 2019). PMID: 30910934.

Cina, D., Ketela, T., Brown, K.R., Chandrashekhar, M., Mero, P., Li, C., Onay, T., Fu, Y., Han, Z., Saleem, M.A., Moffat, J., and Quaggin, S.E. (2019) Forward genetic screen in human podocytes identifies diphthamide biosynthesis genes as regulators of adhesion. American Journal of Physiology-Renal Physiology (E-pub on Sep. 30, 2019) PMID: 31566424.

Harsh, S., Fu, Y., Kenney, E., Han, Z., and Eleftherianos, I. (2020) Zika virus non-structural protein NS4A restricts eye growth in Drosophila through regulation of JAK/STAT signaling. Disease Model & Mechanisms 13 (4): dmm040816. (E-pub on March 9, 2020) PMID: 32152180.

Fu, Y., Huang, X., Zhang, P., van de Leemput, J., and Han, Z.* (2020) Single-cell RNA sequencing identifies novel cell types in Drosophila Journal of Genetics and Genomics (E-pub on March 9, 2020) PMID: 32487456. (*Corresponding author).

Wen, P., Zhang, F., Fu, Y., Zhu, J.Y., Richman A., Han, Z.* (2020) Exocyst Genes Are Essential for Recycling Membrane Proteins and Maintaining Slit Diaphragm in Drosophila Journal of the American Society of Nephrology 31(5): 1024-1034 (E-pub on April 1^st, 2020) PMID: 32238475. (*Corresponding author).

Manivannan S.N., Darouich, S., Masmoudi, A., Fordon, D., Zender, G., Han, Z., White, P., McBride, K., and Garg, V. (2020) Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy. PLoS Genetics (E-pub on May 26, 2020) PMID: 32453731.

For a complete list of Dr. Han's published work, visit: MyBibliography

The main research interest of Dr. Han is to use the fruit fly Drosophilato to model human diseases, provide functional data for human genetic variants, discovery disease mechanism and develop targeted treatment. Dr. Han’s lab has developed many types of Drosophiladisease models. As a trained developmental biologist, he has tremendous interest in genetic variants that affect the development and function of heart, kidney, blood, muscle and metabolism.

For heart disease, his lab developed the first high-throughput variant function validation system for Congenital Heart Disease. His lab also discovered many new genes required for heart development in flies. For kidney disease, his lab developed the first in vivofunctional assay for Drosophilanephrocytes, which share striking similarities with human glomerular podocytes. His lab is the first to use nephrocytes to model and study human genetic kidney diseases.Work done in Dr. Han’s lab has led to the discovery of several new kidney disease genes, as well as a targeted treatment for a specific type of genetic kidney disease.

For blood, muscle and metabolism, Dr. Han’s lab developed novel functional assays and fly models to study genetic variants involved in leukemia, congenital muscular dystrophy, and different types of metabolic diseases. The long-term goal of Dr. Han’s research is to establish Drosophilaas a primary model system for providing the much-needed functional data for large number of genetic variants identified from patient sequencing, and to useDrosophiladisease models to discover underlying mechanism, and then to test mechanism-based targeted treatment using fly models.

Society Memberships

• 1998 – present: Genetic Society of America
• 1999 – present: American Heart Association
• 2006 – present: Society of Chinese Bioscientists in America
• 2011 – present: American Society of Nephrology
• 2016 – present: American Society of Human Genetics

Academic Honors

• 1997: University of Michigan Horace H. Rackham School of Graduate Studies, Pre-Doctorial Fellowship
• 2001: American Heart Association, Council on Cardiovascular Disease, Weinstein Cardiovascular Development Research Conference, Travel Award
• 2003: Pathways to Cardiac Development and Regeneration Conference, Young Investigator Award
• 2006: Genetics Society of America, 47^thAnnual Drosophila Research Conference, Best present:ation Award
• 2006: University of Michigan Biomedical Sciences Scholar
• 2015: First Sino-US-Japan Pediatric Translational Medicine Forum, Lecture Award
• 2017: Children’s National Health System, Children’s Research Institute 2017 Major Scientific Advances
• 2019: University of Maryland School of Medicine (UMSOM) Special Trans-Disciplinary Recruitment Award Program (STRAP) awardee

Major Research Awards

• 2001: American Heart Association Midwest Affiliate, Pre-Doctorial Fellowship
• 2003: American Heart Association Texas Affiliate Post-Doctorial Fellowship
• 2006: American Heart Association National Center, National Scientist Development Award
• 2007: University of Michigan McKay Cardiovascular Research Grant Award
• 2008: National Institute of Health (NIH) R01 Award, R01-HL090801: “A novel G protein signaling pathway controlling Drosophila cardiac morphogenesis”. Role: Principle Investigator. 
• 2009: National Institute of Health (NIH), American Reinvestment and Recovery Act Administration (ARRA) Supplement Award, R01-HL090801S: “Secretion pathway genes in Drosophila cardiac morphogenesis”, Role: Principle Investigator. 
• 2014: National Institute of Health (NIH) R01 Award, R01-DK098410: “Drosophila, a new genetic model for glomerular diseases and drug discovery”. Role: Principle Investigator. 
• 2017: National Institute of Health (NIH) R01 Award, R01-HL134940: “Ancestral roles of histone-modifying genes in heart development and disease”. Role: Principle Investigator. 
• 2017: National Institute of Health (NIH) R01 Award, R01- DK105055: “Anti-fibrotic action of SARA”.Role: Site PI.
• 2018: National Institute of Health (NIH) R01 Award, R01-DK098410: “Modeling Nephrotic Syndrome in Drosophila nephrocytes”. Role: Principle Investigator.
• 2018: National Institute of Health (NIH) R01 Award, R01-DK115968: Novel mechanisms and Drosophila model of APOL1-HIV-1 nephropathies in children”. Role: Multi PI.
• 2019: National Institute of Health (NIH) R01 Award, R01- DK120908: “Integrating Drosophila and human podocyte studies to discover APOL1 renal toxicity”. Role: Principle Investigator.
• 2019: National Institute of Health (NIH) INCLUDE Supplement Award, R01-HL134940S: “Using Drosophila heart to map candidate genes associated with Down Syndrome Congenital Heart Disease”. Role: Principle Investigator. 

Community Service Award

• 2017: Thomas Jefferson High School for Science and Technology, Mentorship Program Award

Active Grants

Han, Zhe (single PI) R01-DK098410
4/10/2014 – 7/31/2023
Modeling Nephrotic Syndrome in Drosophila nephrocytes
National Institute of Health (NIH), National Institute of Diabetes and Digestive and Kidney diseases (NIDDK)
Yearly Direct Costs of Award: $225,000
Role: PI (single-PI)
Percent Effort: 20%
The goal of this project is to establish the Drosophila nephrocyte as a primary model system for modeling nephrotic syndrome caused by genetic mutations in humans.

Han, Zhe (single PI) R01-HL134940
7/20/2017 – 6/30/2021
Ancestral roles of histone-modifying genes in heart development and disease
National Institute of Health (NIH), National Heart Lung and Blood Institute (NHLBI)
Yearly Direct Costs of Award: $250,000
Role: PI (single-PI)
Percent Effort: 20%
Mutations in histone-modifying genes have been identified as a major risk factors from the genomic sequencing of Congenital Heart Disease (CHD) patients, but the roles of histone modifying genes in heart development remain unclear. The goal of this project is to study the role of histone-modifying genes in heart development, using Drosophila as a model system. We will also establish a series of fly models of Congenital Heart Disease, using the exact same histone modifying gene mutations identified from the patients, to better understand the disease mechanisms.

Han, Zhe (site PI) R01-DK105055
8/1/2017 – 7/31/2021
Anti-fibrotic action of SARA
Yearly Direct Costs of Award: $50,000
Role: Site-PI (PI: H William Schnaper, Northwestern University)
Percent Effort: 5%National Institute of Health (NIH), National Institute of Diabetes and Digestive and Kidney diseases (NIDDK)
Fibrosis, the process of scarring, is a common mechanism by which kidney injury progresses to kidney loss. We discovered that a signaling molecule, Smad anchor for receptor activation, or SARA, might maintain kidneys in a healthy state by preventing them from producing scar when they are damaged.
The goal of this project is to better understand the way SARA acts in the tissues to oppose scarring, to learn what makes SARA levels go up or down, and to identify the actions of SARA using Drosophila and mouse as model systems.

Han, Zhe (multi-PI) R01-DK115968
9/15/2018 – 6/30/2023
Novel mechanisms and Drosophila model of APOL1-HIV-1 nephropathies in children
National Institute of Health (NIH), National Institute of Diabetes and Digestive and Kidney diseases (NIDDK)
Yearly Direct Costs of Award (to the Han lab): $178,000
Role: Multi-PI, with Dr. Patricio Ray at the University of Virginia
Percent Effort: 20%
The goal of this project is to develop the Drosophila HIV-1 nephropathy models and use it to study the molecular mechanism of HIV-associated nephropathy.

Han, Zhe (single PI) R01- DK120908
3/1/2019 – 12/31/2022
Integrating Drosophila and human podocyte studies to discover APOL1 renal toxicity mechanism and therapeutic targets
National Institute of Health (NIH), National Institute of Diabetes and Digestive and Kidney diseases (NIDDK)
Yearly Direct Costs of Award: $225,000
Role: PI (single-PI)
Percent Effort: 20%
The goal of this project is to develop the Drosophila model APOL1 nephropathy model and use it to study the molecular mechanism of APOL1-associated nephropathy.

UM School of Medicine Researchers Identify Mechanism to Explain Role of Certain Gene Mutations in Kidney Disease (Public Release: April 03, 2020) Link: https://www.medschool.umaryland.edu/news/2020/UM-School-of-Medicine-Researchers-Identify-Mechanism-to-Explain-Role-of-Certain-Gene-Mutations-in-Kidney-Disease.html

UM School of Medicine Scientist Receives NIH Award to Study Heart Disease Related to Down Syndrome
September 25, 2019

NUP160 genetic mutation linked to steroid-resistant nephrotic syndrome
March 26, 2019
Children's National
American Association for the Advancement of Science (AAAS)
Brightsurf.com

$2 million NIH grant for treating disease linked to APOL1
April 2, 2019
Children's National
American Association for the Advancement of Science (AAAS)

Research led by Zhe Han featured on cover of JASN, leading kidney disease journal  
December 5, 2017

Lab led by Zhe Han, Ph.D., receives $1.75 million from NIH to continue pioneering research
July 31, 2017

Supplement can lessen kidney damage linked to genetic mutations in transgenic fruit flies
April 20, 2017

Studying fruit flies to better understand human kidneys
April 6, 2017

Drosophila effectively models human genes responsible for genetic kidney diseases
March 17, 2017

High-throughput, in vivo validation of candidate congenital heart disease genes
February 9, 2017

APOL1 linked to reduced nephrocyte function, increased cell size, accelerated cell death
November 18, 2016

• 2017 – present: Chair, National Membership Committee, Society of Chinese Bioscientists in America (SCBA)
• 2015 – present: Member, Board of Directors, Society of Chinese Bioscientists in America (SCBA) DC-Baltimore Chapter
• 2015 – 2019: Member, Mentorship Program, Thomas Jefferson Magnet High School for Science & Technology (TJHSST)
• 2016 – 2017: Chair, Scientific Committee, Society of Chinese Bioscientists in America (SCBA) DC-Baltimore Chapter
• 2017: Organizer, 2017 SCBA DC-Baltimore Chapter Scientific Symposoium
• 2020: Organizer, 2020 SCBA DC-Baltimore Chapter Scientific Symposoium 

I am a trained developmental biologist with a research program focused on using Drosophilato model human diseases and to identify precision medicine-based therapeutic targets. Our long-term focus has been on heart and kidney diseases caused by genetic mutations. Over the past 13 years as an independent PI, I have made seminal contributions that establishedDrosophilaas an important model system for heart and kidney diseases. My lab is the first to discover that the Drosophilacardiac nephrocyte functions as the key cell type for filtration and protein reabsorption, and can be used to identify novel genes required for kidney functions (A1).

To establish the relevance of using Drosophilanephrocytes to model Nephrotic Syndrome (NS), we performed a functional screen of all known NS genes, and discovered that 85% of these NS genes have fly homologs required for nephrocyte function, suggesting that nephrocytes can be used to model a majority of glomerular kidney diseases (A2). To take the unique advantage of the powerful genetic tools and rich genetic resources available for Drosophila, we developed a novel “Gene Replacement” approach to make personalized Drosophilamodels that carry patient-derived mutant alleles, specifically in the nephrocyte, for mechanism studies and drug testing (A3). We successfully rescued a personalized fly model for a specific COQ2 gene mutation from a NS patient, using Q₁₀supplement as a targeted treatment (A3). We also generated transgenic fly lines that express risk alleles of APOL1, the gene that is responsible for higher renal disease risk in African Americans (A4). We showed that expression of APOL1-G1in nephrocytes induced hypertrophy, accelerated cell death, and caused abnormal organelle acidification (A4).

In our unpublished preliminary studies for this proposal, we showed that our APOL1 fly models are highly relevant to the recent published mouse model and human APOL1 nephropathy patients. It appears that the APOL1 renal toxicity mechanism is conserved from flies to humans. The fly model provides a unique opportunity to conduct genetic screen to identify genes that could antagonize the APOL1 toxicity and therefore be developed as potential gene therapy treatment. My lab also developed human embryonic kidney and podocyte culture system to validate the finding from our Drosophilanephrocyte screen. Therefore, we have established a highly unique fly to human discovery system for screening and testing potential therapeutic target genes for APOL1 nephropathy, to help the field to tackle this significant type of renal disease that affects millions of African Americans.  

• A1. Zhang, F., Zhao, Y., and Han, Z.(2013). Anin vivofunctional analysis system for renal gene discovery in Drosophilapericardial nephrocytes. Journal of the American Society of Nephrology24, 191-197. PMID: 23291470.
• A2. Fu, Y., Zhu, J.Y., Richman, A., Zhao, Z., Zhang, F., Ray, P.E., Han, Z.(2017) A Drosophilamodel system to assess the function of human monogenic podocyte mutations that cause nephrotic syndrome. Human Molecular Genetics(E-published on Feb. 6, 2017). PMID: 28164240. 
• A3. Zhu, J.Y., Fu, Y., Richman, A., Zhao, Z., Ray, P.E., and Han, Z.(2017) A personalized Drosophilamodel of COQ2nephropathy rescued by the wild-type human COQ2allele and dietary Q₁₀supplementation. Journal of the American Society of Nephrology (E-published on April 20, 2017). PMID: 28428331.
• A4. Fu, Y., Zhu, J.Y., Richman, A., Zhang, Y., Xie, X., Das, J.R., Li, J., Ray, P.E., and Han, Z.(2017) APOL1-G1in nephrocytes induces hypertrophy and accelerates cell death. Journal of the American Society of Nephrology(E-published on Nov. 18, 2016). PMID: 27864430.

Establish the Drosophilanephrocyte as a model to study podocyte biology. 

My lab discovered that fluorescent proteins secreted into the hemolymph accumulate in cardiac nephrocytes. Based on this observation we generated the first in vivorenal functional readout (a transgenic fly line called pMAR), and performed the first genetic screen for genes required for kidney filtration functions (C1.1). In this study, we should that the nearly all key slit diaphragm components are highly conserved from flies to humans, and that the Drosophilanephrocyte is a highly efficient model to identify and study genes involved in kidney filtration function (C1.1). We also discovered that in addition to the filtration function, the Drosophilanephrocyte also has protein reabsorption function, using the same receptors (Cubilin and AMN) that are used in human renal proximal tubule cells (C1.2). In collaboration with Dr. Patricio Ray at Children’s National, we tested TNF-α in fly nephrocytes (C1.3). We also screened all 30 genes encoding the Rab GTPases (key cell traffic regulators) and identified the critical endocytic trafficking pathways for nephrocytes, and compared them with human podocytes (C1.4). In our unpublished studies, we identified over 30 genes that either construct or regulate the cytoskeleton of nephrocytes. Many of them have highly conserved human homologs that are expressed in human podocytes. We are testing the function of these genes in both Drosophilanephrocytes and cultured human podocytes. These studies established the Drosophilanephrocyte as a powerful tool to study podocyte biology, with many unique advantages to complement the other systems including zebrafish, mouse and cultured podocytes: 1. Low-cost high-efficiency in vivosystem; 2. Slit diaphragm within a single cell; 3. Quick and easy gene modification and genetic interaction assays; 4. Live cell imaging for filtration function;  5. Ability to do genetic screen for genes involved in a particular readout; 6. Modifier screen to identify cofactor or regulators for a introduced gene; 7. Easy access for RNA-seq from a pure nephrocyte population to identify downstream targets.

• C2 1: Zhang, F., Zhao, Y., and Han, Z. (2013). An in vivofunctional analysis system for renal gene discovery in Drosophilapericardial nephrocytes. Journal of the American Society of Nephrology24, 191-197. PMID: 23291470. (Highlighted In issue 24 by JASN editors: “Drosophilafacilitate study of podocytes”,).
• C2 2: Zhang, F., Zhao, Y., Chao, Y., Muir, K., and Han, Z. (2013). Cubilin and Amnionless mediate protein reabsorption in Drosophilanephrocytes. Journal of the American Society of Nephrology24, 209-216.PMID: 23264686. PMCID: PMC3559489.
• C2 3: Li, J., Das, J.R., Tang, P., Han, Z., Jaiswal, J.K., Ray, P.E. (2016) Transmembrane TNF-α facilitates HIV-1 infection of podocytes cultured from children with HIV-associated nephropathy. Journal of the American Society of Nephrology(E-published on Nov. 3, 2016). PMID: 27811066.
• C2 4: Fu, Y., Zhu, J.Y., Zhang, F., Richman, A., Ray, P.E., Zhao, Z., and Han, Z.(2017) Comprehensive functional analysis of Rab GTPase genes in Drosophilanephrocytes. Cell & Tissue Research(E-published on Feb. 8, 2017). PMID: 28180992.

Establish Drosophilaas a unique animal model for genetic kidney diseases

The Drosophilasystem has the most powerful genetic tools and richest genetic resources, as a result of being developed as a genetic model system for the past 150 years. It has been used to model many types of human diseases. However, for the most time of the past 150 years, the fly community was unaware of the presence of filtration kidney cells in Drosophila, until Helen Skaer’s lab discovered that the insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm (Weavers et al.,Nature2009). The generation of the in vivofunctional readout of nephrocytes in my lab (Zhang et al., JASN2013) enabled a highly efficient way for testing the function of any genes in Drosophilanephrocytes. Using this approach, by collaborating with human geneticist who are sequencing kidney disease patients to identify novel kidney disease genes, we provided the in vivofunctional data for a series of novel kidney disease genes, including ARHGDIA,ADCK4and KANK2, to help establish these genes as novel nephrotic syndrome genes. These works have led to three papers published in Journal of Clinical Investigation(JCI). In one of these JCI papers, our fly data not only provided the in vivofunction evidence of the KANK2 gene, but also suggested the involvement of KANK2 in actin cytoskeleton regulation, which led to the discovery of the molecular mechanism and potential therapeutic treatment (C2.1). To establish a clear relevance of the Drosophila nephrocyte to disease genes that affect human podocytes, we performed a functional screen of 40 known Nephrotic Syndrome (NS) genes identified over the past 20 years. We showed that 85% of these NS genes have fly homologs required for nephrocyte function, suggesting that nephrocytes can be used to model most human genetic diseases affecting podocytes (C2.2). With the unique advantage of the powerful genetic tools available in Drosophila, we developed a “Gene Replacement” approach to make personalized Drosophilamodels that carry patient-derived mutant alleles, and used it for drug testing (C2.3). We successfully generated a personalized fly model for a specific COQ2 gene mutation from a NS patient, and rescued the renal defects of this fly model using Q₁₀supplement as a treatment (C2.3). This study was featured on the cover of JASN (2017 September issue).  We also generated Drosophilamodel of APOL1 nephropathy, which affect millions of people that are African decedents. We showed that expression of APOL1 risk alleles in nephrocytes induced many phenotypes that are relevant to human APOL1 patients, including kidney cell hypertrophy, accelerated cell death, and abnormal organelle acidification (C2.4). Using the powerful genetic tools in Drosophila, we designed and performed a large-scale genetic screen to identify modifying genes for APOL1 toxicity, and discovered many interesting hits that could potentially be used as a gene therapy target to antagonize APOL1 renal cell toxicity.

• C2 1: Gee, H.Y., Zhang, F., Ashraf, S., Kohl, S., Sadowski, C., Vega-Warner, V., Zhou, W., Fang, H., Lovric, S., Hoefele, J., Weber, L., Podracka, L., Boor, A., Innis, J., Washburn, J., Salviati, L., William, D.S.,Levy, S., Otto, E., Han, Z.^#, and Hildebrandt, F.^#(2015) KANKdeficiency leads to defective podocyte function and nephrotic syndrome. Journal of Clinical Investigation125, 2375-2384. PMID: 25961457. (^#co-corresponding author).
• C2 2: Fu, Y., Zhu, J.Y., Richman, A., Zhao, Z., Zhang, F., Ray, P.E., Han, Z.(2017) A Drosophilamodel system to assess the function of human monogenic podocyte mutations that cause nephrotic syndrome. Human Molecular Genetics(E-published on Feb. 6, 2017). PMID: 28164240. 
• C2.3. Zhu, J.Y., Fu, Y., Richman, A., Zhao, Z., Ray, P.E., and Han, Z.(2017) A personalized Drosophilamodel of COQ2nephropathy rescued by the wild-type human COQ2allele and dietary Q₁₀supplementation. Journal of the American Society of Nephrology (E-published on April 20, 2017). PMID: 28428331.(Featured on the cover of JASN for the September 2017 issue).
• C2.4. Fu, Y., Zhu, J.Y., Richman, A., Zhang, Y., Xie, X., Das, J.R., Li, J., Ray, P.E., and Han, Z.(2017) APOL1-G1in nephrocytes induces hypertrophy and accelerates cell death. Journal of the American Society of Nephrology(E-published on Nov. 18, 2016). PMID: 27864430.

C3. Using Drosophilato study genetic control of heart development

My team conducted large-scale genetic screen for novel genes involved in Drosophilaheart development (Yi et al., Science2006; C4.1). We discovered many new genes involved in heart development and characterized them over the past 12 years and published extensively in this direction. Among them, we discovered a novel heart- and muscle-specific microRNA, miR-92b, as a key regulator of the critical transcription factor Mef2 that controls heart and muscle differentiation from flies to humans (C3.1), a conserved WNT pathway component, WNT4, which we showed to be an essential regulator in the development of ostia, cardiac valve-like structures in the fly heart (C3.2), and an aorta-specific GPCR called Gia which is essential for aorta patterning and pericardial cell positioning (C3.3). Following up with my earlier work on the heart-specific microRNA miR-1, in collaboration with Dr. Isabelle King we discovered that the role of miR-1 in heart development is mediated through negative regulation of the E3 ubiquitin ligase Nedd4 (C.3.4). These studies, together with over 15 papers I coauthored over the past 20 years, characterized some of the most important genetic regulators of heart development. Many of them are highly conserved from flies to humans, and provided valuable insights into heart disease mechanisms associated with mutations or drugs that interfere with cardiac gene or microRNA functions.

• C3.1.  Chen, Z., Liang, S., Zhao, Y., and Han, Z.(2012). MiR-92b regulates Mef2 levels through a negative feedback circuit during Drosophilamuscle development. Development139 (19): 3543-3552. PMID: 22899845.
• C3.2.  Chen, Z. Zhu, J.Y., Fu, Y., Richman, A., and Han, Z.(2016) Wnt4is required for ostia development in the Drosophilaheart. Developmental Biology413, 188-198. PMID: 26994311.
• C3.3. Patel, M.V., Zhu, J.Y., Jiang, Z., Richman, A., VanBerkum M.F. and Han, Z.(2016) Gia/Mthl5 is an aorta specific GPCR required for Drosophilaheart tube morphology and normal pericardial cell positioning. Developmental Biology414, 100-107. PMID: 26994946.
• C3.4.  Zhu, J.Y., Heidersbach, A., Kathiriya, I.S., Garay, B.I., Ivey, K.N., Srivastava, D., Han, Z.*, and King, I.N.* (2017) The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA-1. Development144, 866-875. (*Co-corresponding author, E-published on Mar. 1, 2017). PMID: 28246214.

C4. Establish Drosophilaas a unique animal model for Congenital Heart Disease (CHD)

My research in heart development is strongly motivated by the use of flies to elucidate molecular mechanisms of CHD, the most common birth defect. My team screened thousands of mutations for effects on fly heart development and identified many novel cardiogenic genes. Some of these genes constitute a conserved pathway of geranyl-geranyl lipid synthesis (with HMGCR as the rate limiting enzyme) that is critical for modification of Ggamma1 essential for fly heart development, which provided the molecular mechanism for the high risk of CHD babies from pregnant women taking statins (C4.1). Recently, hundreds of new candidate CHD genes have been identified from large-scale genomic sequencing projects, but the lack of a highly efficient animal model system to provide functional data hindered the progress of the field. My lab developed a high-throughput in vivofunctional validation system using the Drosophilaheart, to provide the much needed functional data for these candidate CHD genes (C4.2). We also developed many new morphologic and functional readout for the Drosophilaheart so that the phenotype can be better compared with the patients (C4.3). Most recently, together with Dr. Vidu Garg’s lab at the Nationwide Children’s, we discovered an epigenetic mechanism involving Notch pathway and the histone modifyig gene Jarid2, which could provide the explaination for the much higher risk of CHD babies from diabetic mothers (C4.4), using the unique advantages of Drosophilagenetic tools and quick transgeneration genetic assays.

• C4.1. Yi, P.*, Han, Z.*#, Li, X., Olson, E. N#. (2006). The Mevalonate Pathway Controls Heart Formation in Drosophilaby Isoprenylation of Ggamma1. Science313 (5791): 1301 – 1303. PMID: 16467358 (*Co-first author and # co-corresponding author).
• C4.2. Zhu, J.Y., Fu, Y., Nettleton, M., Richman, A., and Han, Z.(2017). High throughput in vivofunctional validation of candidate congenital heart disease genes in Drosophila.eLife(E-published on Jan. 13, 2017). PMID: 28084990.
• C4.3. Zhu, J.Y., Fu, Y., Richman, A., and Han, Z*.(2017). Validating candidate congenital heart disease genes in Drosophila. Bio Protocol(E-published on June 20, 2017), Vol 7, Issue 12. PMID: 29276722.  (*Corresponding author).
• C4.4. Basu, M., Zhu, J.Y., LaHaye, S., Majumdar, U., Jiao, K., Han, Z.*,and Garg, V.* (2018) Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease. JCI Insight2(20), E-published on Oct. 19, 2017. PMID: 29046480. (*Co-corresponding author).