Salil A. Lachke, Ph.D.

Teaching

BISC401/BISC609: Molecular Biology of the Cell (Course Website available through Canvas)

Research Interests

Second only to mental illnesses, we largely fear losing our sense of sight (Horowitz et al. 1997, Cepko 2001).  Loss of vision is detrimental and can result from a functional compromise of various components of the eye.  However, opacification of the transparent lens – clinically termed cataract – remains the leading cause of blindness in the world.  Cataract affects over millions of individuals worldwide and its incidence continues to rise with increase in human life expectancy.  Surgery remains the only treatment, carrying with it the risk of secondary cataract formation – an undesirable complication, especially in the elderly.  Therefore, strategies to prevent or delay the onset of this disease need to be designed, a challenge for which comprehensive understanding of the development and maintenance of this unique tissue is essential.

My laboratory uses systems-based approaches for the identification and functional elucidation of genes involved in organ development and disease. We have developed a bioinformatics-based approach termed "iSyTE" (integrated Systems Tool for Eye gene discovery, https://research.bioinformatics.udel.edu/iSyTE/) and have successfully used it to identify novel cataract genes and predict several uncharacterized genes with potential function in lens development.  Our goal is to characterize these candidate genes using biochemical, molecular, cell biological and genomics-level approaches.  As an important step towards this goal, we have used iSyTE to highlight the involvement of several new regulators, including TDRD7 (a post-transcriptional regulatory protein and RNA granule component) and CELF1 (a post-transcriptional regulatory protein and RNA-binding protein) in lens differentiation and cataractogenesis (Lachke et al. 2011, Science 331:1571-76 View in: Pubmed, Siddam et al. 2018, PLoS Genetics 14(3):e1007278 View in: Pubmed).  Our long-term goal is to deduce the gene regulatory networks (GRNs) that underlie organogenesis, which will need to be resolved in order to devise new regenerative therapies for diseases that affect these tissues.  Besides its clinical significance, we anticipate that insights gained from this research can potentially unveil basic regulatory principles relevant to the differentiation of other cell and tissue types.

Current Projects

Project 1:  Elucidate the function of cytoplasmic RNA-binding proteins and RNA granules in the lens.  iSyTE has predicted several uncharacterized lens-enriched components of RNA granules (RGs).  In this project, we seek to comprehensively define the different classes of RGs present in the developing lens.  We then aim to identify RNA targets of specific RG components and RNA binding proteins (RBPs) in the lens AEL and FCs.  This research is expected to make a major contribution to the field by generating binding motifs for several RBPs and by identifying their functional targets in the context of a developing tissue.

Project 2. Define the CELF1 and TDRD7 interactome and target RNAs in the lens.  In these projects, we aim to characterize the total repertoire of differentially regulated RNAs (including mRNAs and small RNAs) in Tdrd7 and Cefl1 null mutant lenses by expression profiling.  We also aim to define the CELF1 and TDRD7 lens interactome by using well-established proteomics-based protocols to identify the protein binding partners of CELF1 and TDRD7.  Identification of the critical nodes interacting with CELF1 and TDRD7 should have significant impact in providing insight into the post-transcriptional control of gene expression in lens development.

Project 3: Building a Gene Regulatory Network (GRN) for the developing lens.  We aim to use chromatin immunoprecipitation (ChIP), RNA-immunoprecipitation (RIP) coupled with expression analysis, protein binding microarrays, computational approaches and reporter analysis to define the nodes and edges functional in the lens GRN.  In our efforts to build a comprehensive GRN for the developing lens we seek to determine the regulators (transcription factors (TFs) and RBPs) and their target cis-Regulatory Modules (CRMs) that function to control lens expressed genes.

Watch a video summary of Dr. Lachke's research here.

Watch Dr. Lachke's lecture on the 2012 Nobel prize winning work of Dr. John Gurdon and Dr. Shinya Yamanaka here.

If you are an ARVO member, watch Dr. Lachke's presentation in the 2015 ARVO minisymposium "Integrated genomic networks in eye development and pathogenesis" here.

Watch Dr. Lachke's seminar in the Innovative Discoveries Series, at the Delaware Clinical & Translational Research ACCEL Program and the Christiana Care Value Institute here.

Read the NIH Director Dr. Francis Collins' comments on Dr. Lachke's research in the NIH Director's Blog

Research Group

Laboratory Members:

Salil Lachke (PI, Faculty Mentor)

Deepti Anand (Postdoctoral Fellow)

Salma Al Saai (Graduate Student)

Sandeep Aryal (Graduate Student)

Shaili Patel (Graduate Student)

Kimia Ahmadizadeh (Graduate Student)

Priyanka Ghorpade (Graduate Student)

Francisco Hernandez (Undergraduate Student)

Sabrina Luther (Undergraduate Student)

Emily Paglione (Undergraduate Student)

Juan Ruiz (Undergraduate Student)

Campbell Toensing (Undergraduate Student)

Bailey Weatherbee (Undergraduate Student)

Lachke Laboratory Alumni:

Soma Dash (Graduated with Ph.D. 2013-2018) (Placement: Postdoc with Dr. Paul Trainor at Stowers Institute for Medical Research, Kansas City, MO - The Trainor lab is a leading lab in the world for craniofacial and neural crest cell research)

Dominic Villalba (Undergraduate Senior Thesis 2016-2018) (Placement: Research Technician with Dr. Raymond Penn at Sidney Kimmel Medical College at Thomas Jefferson University)

Archana Siddam (Graduated with Ph.D. 2012-2017) (Placement: FDA (U.S. Food and Drug Administration) Director's Fellowship - a highly competitive and prestigious fellowship awarded to select 15 in 2017 across the United States)

Nathaniel Borders (Undergraduate Honors Thesis 2015-2017) (Placement: Research Assistant, Harvard Medical School, George Church Laboratory - the Church lab is at the forefront of biomedical technologies research in the world)

Joshua Barton (Undergraduate Honors Thesis 2014-2016) (Placement: M.D., Ph.D. Program, Sidney Kimmel Medical College at Thomas Jefferson University)

Anne Terrell (Research Associate II, 2013-2015) (Placement: Preceptor, University of Delaware)

Carrie Barnum (Graduated with M.S. 2012-2015) (Placement: Research Associate, University of Pennsylvania)

Sheila Sichani (Undergraduate Research 2014-2015) (Placement: Intern, Agilent Biotech)

Smriti Agrawal (Graduated with M.S. 2012-2014) (Placement: Doctoral Student, Baylor College of Medicine; had also recieved admissions in the doctoral programs at the University of Washington-Seattle and the University of California-Berkeley)

Christine Dang (Undergraduate Honors Thesis 2012-2014) (Placement: M.D. Program, Sidney Kimmel Medical College at Thomas Jefferson University)

Shaili Patel (Undergraduate Senior Thesis 2013-2014) (Placement: Research Associate, University of Pennsylvania)

Sylvie Smith (Undergraduate Student, Research 2014) (Placement: Associate Laboratory Technician, WuXi AppTec)

Stephanie Waters (Research Associate II, 2011-2013) (Placement: Associate Scientist, DuPont)

Selected Publications

  • 2018 (Total 14: 8 accepted/published, 3 in review/revision, 3 in prep.)
  • In Preparation (3)
  • Dash S, Brastrom LK, Patel, SD, Scott CA, Slusarski DC, Lachke SA. The RNA-binding protein Rbm24 post-transcriptionally regulates Sox2 mRNA stability by directly interacting with its 3'UTR AU-rich elements to control vertebrate eye development. PLoS Genetics 2018: Prepared for submission
  • Siddam AD, Barton JR, Weatherbee BAT, Anand D, Lachke SA. Molecular characterization of the human lens epithelial cell line SRA01/04. Experimental Eye Research 2018: Prepared for submission
  • Barnum CE, Al Saai S, Cheng C, Anand D, Patel SD, Dash S, Siddam AD, Glazewski L, Polson S, Chuma S, Mason RW, Batish M, Fowler VM, Lachke SA. The Tudor-family protein TDRD7, mutated in congenital cataract and azoospermia, regulates the heat shock protein Hspb1 is necessary for F-actin cytoskeleton maintenance in lens fiber cell differentiation. Human Molecular Genetics 2018: Prepared for submission
  • Submitted/In Review/Revision (3)
  • Carlson JC, Anand D, Buxo CJ, Christensen K, Deleyiannis F, Hecht JT, Moreno LM, Orioli LM, Padilla C, Shaffer JR, Vieira AR, Wehby GL, Weinberg SM, Murray JC, Beaty TH, Saadi I, Lachke SA, Marazita ML, Feingold E, Leslie EJ. Phenotypic heterogeneity in orofacial clefts: a novel method for systematic genetic analysis and visualization of heterogeneity. Genetic Epidemiology 2018: In revision View in: Preprint server
  • Ewans LJ, Colley A, Gaston-Massuet C, Gualtieri A, Cowley MJ, McCabe MJ, Anand D, Lachke SA, Scietti L, Forneris F, Zhu Y, Ying K, Walsh C, Lee E, Kirk EP, Field M, Miller D, Giunta C, Sillence D, Dinger ME, Buckley M, Roscioli T. Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue dysplasia with vascular complications. Genetics in Medicine 2018: Submitted
  • Cox TC, Lidral A, Liu H, Cox LL, Zhu Y, Moreno Uribe LM, Anand D, Deng M, Richter CT, Nidey NL, Standley JM, Blue EE, Chong JX, Smith JD, Kirk EP, Venselaar H, Krahn KN, van Bokhoven H, Zhou JH, Cornell RA, Glass IA, Bamshad MJ,  Nickerson DA, Murray JC, Lachke SA, Buckley MF, Roscioli T. Mutations in GDF11 and its binding partner, FST, as a cause of orofacial clefting in humans. Human Mutation 2018: Submitted
  • Published/Accepted/In Press (8)
  • Butali A, Mossey PA, Adeyemo WL, Eshete MA, Gowans LJJ, Busch TD, Jain D, Yu W, Huan L, Laurie CA, Laurie CC, Nelson S, Li M, Sanchez-Lara PA, Magee WP 3rd, Magee KS, Auslander A, Brindopke F, Kay DM, Caggana M, Romitti PA, Mills JL, Audu R, Onwuamah C, Oseni GO, Owais A, James O, Olaitan PB, Aregbesola BS, Braimah RO, Oginni F, Oladele AO, Bello SA, Rhodes J, Shiang R, Donkor P, Obiri-Yeboah S, Arthur FKN, Twumasi P, Agbenorku P, Plange-Rhule G, Oti AA, Ogunlewe OM, Oladega AA, Adekunle AA, Erinoso AO, Adamson OO, Elufowoju AA, Ayelomi OI, Hailu T, Hailu A, Demissie Y, Derebew M, Eliason S, Romero-Bustillous M, Lo C, Park J, Desai S, Mohammed M, Abate F, Abdur-Rahman L, Anand D, Saadi I, Oladugba AV, Lachke SA, Amendt BA, Rotimi CN, Marazita ML, Cornell RA, Murray JC, Adeyemo AA.   Genomic analyses in African populations identify novel risk loci for cleft palate. Human Molecular Genetics 2018: in press View in: Pubmed
  • Anand D, Kakrana A, Siddam AD, Huang H, Saadi I, Lachke SA. RNA-sequencing-based transcriptomic profiles of embryonic lens development for cataract gene discovery. Human Genetics 2018: 137:941-954 View in: Pubmed
  • Cox LL, Cox TC, Moreno Uribe LM, Zhu Y, Richter CT, Nidey N, Standley JM, Deng M, Blue E, Chong JX, Yang Y, Carstens RP, Anand D, Lachke SA, Smith JD, Dorschner MO, Quinlan A, Kirk E, Hing AV, Venselaar H, Valencia Ramirez LC, Bamshad MJ, Glass IA, Cooper JA, Haan E, Nickerson DA, van Bokhoven H, Zhou H, Krahn K, Buckley MF, Murray JC, Lidral AC, Roscioli T. Mutations in the epithelial cadherin-p120-catenin complex cause mendelian non-syndromic cleft lip and palate. American Journal of Human Genetics 2018: 102(6):1143-1157 View in: Pubmed
  • Krall M, Htun S, Anand D, Hart D, Lachke SA*, Slavotinek A*. A zebrafish model of foxe3 deficiency demonstrates lens and eye defects with dysregulation of key genes involved in cataract formation in humans. Human Genetics 2018: 137:315-328 View in: Pubmed *Co-corresponding authors
  • Siddam AD, Gautier-Courteille C, Perez-Campos L, Anand D, Kakrana A, Dang CA, Legagneux V, Mereau A, Viet J, Gross JM, Paillard L, Lachke SA. The RNA-binding protein Celf1 post-transcriptionally regulates p27Kip1 and Dnase2b to control fiber cell nuclear degradation in lens development. PLoS Genetics 2018: 14(3):e1007278 View in: Pubmed *Read comments on this paper by 2006 Nobel Laureate Dr. Craig Mello here
  • Anand D, Agrawal SA, Slavotinek A, Lachke SA. Mutation update of transcription factor genes FOXE3, HSF4, MAF and PITX3 causing cataracts and other developmental ocular defects. Human Mutation 2018: 39:471-494 View in: Pubmed *Featured on the Cover, see Cover Art here