- Amrik Sahota
- Position: Research Professor
- Research Focus: Human Molecular Genetics; Molecular Diagnostics
- Click for Lab Website
- Subset Area: Model Organisms | Rodent, Genetics of Human Disease | Kidney/Urinary/Digestive
- Phone: (848) 445-7185
- Address: Life Sciences Building Rutgers University 145 Bevier Road Piscataway, NJ, 08854
- Office: LSB 124
- Fax: (732) 445-1147
Cystine diamides as inhibitors of cystine stone formation
Cystinuria, a genetic disorder of cystine transport, is characterized by excessive excretion of cystine in the urine and recurrent cystine stones in the urinary tract. Treatment for cystinuria has not changed over the past four decades and the available drugs have poor patient compliance due to adverse reactions. We are evaluating a new approach to prevent recurrent cystine stone formation. Our substantive in vitro studies indicate that cystine diamides are potent inhibitors of cystine crystallization, which is a required condition for cystine stone formation. Our ongoing in vivo studies indicate that our lead compound (LH708) from this family is effective in preventing cystine stone formation in Slc3a1 knockout (KO) mice. We are also designing, synthesizing, and evaluating new analogs and prodrugs of cystine diamides with sufficient metabolic stability and oral bioavailability that can effectively inhibit cystine crystallization in vivo and thus prevent cystine stone formation. The most effective inhibitors are being evaluated for their in vivo efficacy, safety, and bioavailability in Slc3a1 KO mice and for their preclinical ADME-Toxicity properties. This is a collaborative project with Dr. Longqin Hu in the Rutgers School of Pharmacy. Our patents related to this work have been licensed to a pharmaceutical company.
Oxalate mimics as inhibitors of calcium oxalate stone formation
Dr. Longqin Hu and I are also developing a novel approach for the inhibition of oxalate crystal growth using oxalate mimics in the Agxt KO mouse model for primary hyperoxaluria. Oxalate is a dead-end metabolic product, but genetic or acquired alterations in oxalate metabolism can have serious adverse effects, particularly on the renal system. Oxalate can complex with calcium to form poorly soluble calcium oxalate (CaOx) and supersaturation of urinary fluid with CaOx, referred to as hyperoxaluria, can lead to the formation of CaOx stones in the urinary tract. Approximately 80% of kidney stones are composed of CaOx. In addition to CaOx stones, deposition of CaOx crystals in the renal parenchyma and tubules can lead to progressive loss of renal function.
Lesch-Nyhan disease (LND) is an X-linked disorder caused by mutations in HPRT1, the gene that encodes the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT). LND affects both the central nervous and renal systems. The renal symptoms can be controlled by allopurinol, but how HPRT deficiency leads to the profound neurobehavioral problems remains unknown. Much of our current understanding of LND has been derived from studies in mouse models, but the existing models only capture some of the features of the corresponding human disease. This may be due to differences in purine metabolism between humans and mice. We are currently evaluating a mouse model that takes these differences into account.
I am board-certified in Clinical Molecular Genetics by the American Board of Medical Genetics and Genomics and in Molecular Diagnostics by the American Board of Clinical Chemistry. I am licensed as a clinical laboratory director in New Jersey, New York, and California. Advances in molecular biology and genetics continue to enhance our understanding of inherited disorders, cancer, and infectious diseases. My colleagues and I have we developed and implemented into clinical practice multiple molecular diagnostic tests based on these advances. Examples include tests for solid tumors, myeloid malignancies, bone marrow transplantation, viral infections, coagulation disorders, fragile X syndrome, pharmacogenetics, and identity testing.
- Publications: Selected publications (from over 90) Evans RM, Emsley CL, Gao S, Sahota A, Hall KS, Farlow MR, Hendrie H (2000). Serum cholesterol, APOE genotype, and the risk of Alzheimer's disease: a population-based study of African Americans. Neurology. 54: 240-242. Sahota A, Gao S, Hayes J, Jindal RM (2000). Microchimerism and rejection: A meta-analysis. Clin Transplant 14: 346-351. Wang L, Raikwar N, Deng L, Yang M, Liang L, Shao C, Evan AP, Stambrook PJ, Sahota A, Tischfield JA (2000). Altered gene expression in kidneys of mice with 2,8-dihydroxyadenine nephrolithiasis. Kidney Int 58: 528-536. Deng L, Yang M, Fründ S, Wessel T, De Abreu RA, Tischfield JA, Sahota A (2001). Dihydroxyadenine urolithiasis in a patient with considerable residual adenine phosphoribosyltransferase activity in cell extracts but with mutations in both copies of APRT. Mol Genet Metab 72: 260-264. Evan AP, Bledsoe SB, Connors BA, Deng L, Liang L, Shao C, Fineberg N, Grynpass MD, Stambrook PJ, Sahota A, Tischfield JA (2001). Sequential analysis of kidney stone disease in the Aprt knockout mouse. Kidney Int 60: 910-923. Wang L, Raikwar N, Yang M, Deng L, McAteer JA, Stambrook PJ, Sahota A, Tischfield JA (2002). Induction of ?-catenin, integrin ?3, integrin ?6, and PDGF-B by 2,8-dihydroxyadenine crystals in cultured kidney epithelial cells. Exp Nephrol 10: 365-373. Tzortzaki EG, Glass D, Yang M, Evan AP, Bledsoe SB, Stambrook PJ, Sahota A, Tischfield JA (2002). Gender- and age-dependent changes in kidney androgen protein mRNA expression in a knockout mouse model for nephrolithiasis. J Histochem Cytochem 50: 1663-1669. Tzortzaki EG, Yang M, Glass D, Deng L, Evan AP, Bledsoe SB, Stambrook PJ, Sahota A, Tischfield JA (2003). Impaired expression of an organic cation transporter, IMPT1, in a knockout mouse model for kidney stone disease. Urol Res 31: 257-261. Tzortzaki EG, Tischfield JA, Sahota A, Siafakas NM, Gordon MK, Gerecke DR (2003). Expression of FACIT collagens XII and XIV during bleomycin-induced pulmonary fibrosis in mice. Anat Rec 275A: 1073-1080. Vernon, HJ, Osborne C, Tzortzaki EG, Yang M, Rittling SR, Denhardt DT, Buyske S, Bledsoe SB, Evan AP, Fairbanks L, Simmonds HA, Tischfield JA, Sahota A (2005). Aprt/Opn double knockout mice: Osteopontin is a modifier of kidney stone disease severity. Kidney Int 68: 938-947. Liang L, Chen J, Vittal R, Selvanayagam ZE, McAteer JA, Deng L, Tischfield JA, Chin K-V, Sahota A (2006). Expression profiling of crystal-induced injury in human kidney epithelial cells. Nephron Physiol 103: 53-62. Ercolani M, Sahota A, Schuler C, Yang M, Evan AP, Reimer D, Barone JG, Tischfield JA, Levin RM (2010). Bladder outlet obstruction in male cystinuria mice. Int Urol Nephrol 42: 57-63. Chen Y, Capizzi S, Yang M,, Deng L, Bledsoe SB, Evan AP, Tischfield JA, Sahota A (2010). 2,8-Dihydroxyadenine nephrolithiasis induces developmental stage-specific alterations in gene expression in mouse kidney. Urology 75: 914-922. Mackinnon AC Jr, Wang YL, Sahota A, Yeung CC, Weck KE (2012). Certification in Molecular Pathology in the United States: An update from the Association for Molecular Pathology Training and Education Committee. J Mol Diagn 14: 541-549. Edvardsson VO, Palsson R, Sahota A (2012). Adenine phosphoribosyltransferase deficiency. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. 2012 Aug 30. Books and book chapters Taylor MW, Sahota A (1989). Cellular resistance to adenine analogues. In "Drug resistance in mammalian cells (Vol 1): Antimetabolites and cytotoxic analogs" (Gupta RS, Ed), CRC Press, Boca Raton, Florida, pp 111-124. Sahota A, Taylor MW (Eds) (1994). Advances in experimental medicine and biology (Vol 370), Plenum Press, New York. Simmonds HA, Sahota AS, Van Acker KJ (1995). Adenine phosphoribosyltransferase deficiency and 2,8-dihydroxyadenine lithiasis. In "The metabolic and molecular bases of inherited disease", 7th ed (Scriver CR et al, Eds), McGraw-Hill, New York, pp 1029-1044. Also 6th ed (1989) and CD-ROM ed (1997). Sahota AS, Tischfield JA, Kamatani N, Simmonds HA (2001). Adenine phosphoribosyltransferase deficiency and 2,8-dihydroxyadenine lithiasis. In "The metabolic and molecular bases of inherited disease", 8th ed (Scriver CR et al, Eds), McGraw-Hill, New York, pp 2571-2584. Sahota A (2005). The APRT gene. In "Caring for patients with adenine phosphoribosyltransferase deficiency" (Cameron JS, Ed). Chapter in booklet published by the Purine Metabolic Patients Association, London, UK. Sahota A, Brooks AI, Tischfield JA (2007). Preparing DNA from mammalian sources. In: Genetic Variation: A Laboratory Manual (Weiner MP, Gabriel SB, Stephens JC, Eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 103-106. Sahota A, Brooks AI, Tischfield JA (2007). Preparing DNA from cell pellets. In: Genetic Variation: A Laboratory Manual (Weiner MP, Gabriel SB, Stephens JC, Eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 107-109. Sahota A, Brooks AI, Tischfield JA, King IB (2007). Preparing genomic DNA from whole blood: Small- and mid-scale extraction. In: Genetic Variation: A Laboratory Manual (Weiner MP, Gabriel SB, Stephens JC, Eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 120-123. Sahota A, Brooks AI, Tischfield JA (2007). Preparing DNA from blood: Large-scale extraction. In: Genetic Variation: A Laboratory Manual (Weiner MP, Gabriel SB, Stephens JC, Eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 124-128. Sahota A, Brooks AI, Tischfield JA (2007). Preparing DNA from saliva. In: Genetic Variation: A Laboratory Manual (Weiner MP, Gabriel SB, Stephens JC, Eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 129-130.
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