Despite our recent advances in Cardiovascular Medicine, the cardiovascular disease remains the leading cause of death in the world. With the break through brought about by The Human Genome project, we are now in a unique position to dissect the genetic causes of cardiovascular diseases to better understand the pathways that lead to disease in human and subsequently try to find therapies tailored to the specific genetic abnormality.
My interest is to identify cardiovascular disorders that have strong familial pattern. We identify kindreds with these disorders and collect DNA samples from the extended family members to proceed with the technique of positional cloning to identify the disease-causing genes.
Thus far, I, and my colleagues have mapped and identified several gene mutation for congenital heart diseases including patent ductus arteriosus and bicuspid aortic valve. Recently my group identified a gene mutation in LRP6, a co-receptor for Wnt, in a kindred with coronary artery disease and several metabolic phenotypes. We have shown that the mutation impairs a signaling pathway known as Wnt. We have created knockin and knockout mouse models of this gene and are conducting in vivo and in vitro functional studies using human cells, in vitro transfection models, human clinical studies as well as studies on lipid and glucose metabolism in mice in collaboration with Dr. Gerald Shulman, The GCRC, and The Mouse Metabolic Phenotyping Center. We are also investigating the genetic causes of premature coronary artery disease in South Asians. South Asians suffer largely from coronary artery disease in young ages and have high risk for developing diabetes, a constellation of phenotypes commonly referred to as metabolic syndrome. Our preliminary data suggests, that we have identified at least one gene locus for this disorder. We are currently collaborating with several medical centers across the world and in India to recruit new families and individuals with premature coronary artery disease with or without metabolic syndrome to refine the mapped region and identify the gene mutation.
We use several different techniques in our laboratory, which includes positional cloning using DNA microarrays, techniques used for protein chemistry, subcloning, tissue culture, confocal microscopy, FACS, real time PCR and animal model.
Extensive Research Description
My laboratory’s major focus is the identification of genetic causes of major cardiovascular disorders and the elucidation of their pathophysiology. To achieve this, we have built strong ties at national and international levels with major cardiovascular centers. The goal is to identify and recruit patients and families with diverse cardiovascular disorders that have strong genetic components. Through collaborative efforts with physicians and scientist across the world we have recruited large populations of patients and families with early onset coronary artery disease and metabolic syndrome and have successfully mapped and identified number of genes for these diseases. An ongoing effort in the laboratory is to understand the function of these genes and how the mutations affect the phenotype.
In addition my laboratory studies the genetic studies of congenital heart disease. We have mapped and identified disease genes for syndromic and nonsyndromic, autosomal dominant and recessive patent ductus arteriosus and have identified number of novel copy number variations for the bicuspid aortic valve.
My lab has identified one of the first disease genes for early onset coronary artery disease and metabolic syndrome. The mutation (R611C) resides at a highly conserved residue of the second EGF-like domain in the LDL receptor like protein (LRP6), which encodes a co-receptor in the Wnt signaling pathway. Genotype phenotype correlation showed that the mutation impacts number of the metabolic phenotypes that are present in the affected members of the kindred. These findings have established a causal link between Wnt signaling impairment caused by LRP6 mutation and coronary artery/metabolic syndrome and raise the possibility of complex downstream effects of the mutation, which has motivated further investigation.
Having unique access to the genetic study population, we have had the opportunity to carry out clinical studies to investigate the disease mechanisms and have made numerous novel discoveries, published in top ranked journals. We have shown that Wnt signaling regulates the insulin receptor transcription and its reduced expression in human causes diabetes. We have also generated a mouse model of the disease and have shown that Wnt signaling is a nutrient sensing pathway that regulates insulin signaling, glucose metabolism and cholesterol synthesis and, lipogenesis and VLDL secretion. Through investigation of heterozygote mice with we have understood how adipose tissue and liver communicate through leptin receptors to adjust the hepatic gluconogenesis. Hyperinsulinemic clamps are used to examine the contribution of different insulin sensitive tissues to glucose homeostasis.
We have also shown that LRP6 is required for normal function of the LDLR and LDL uptake. This was the first demonstration of LRP6 as an endocytic molecule.
The most exciting development in our lab was the generation of a novel atherosclerotic mouse model. Mouse with mutant LRP6 mutation have diffuse atherosclerosis that could be recued by Wnt3a therapy. In addition we have recently identified 2 novel genes for CAD that are being currently studied for their function.
- 14. Singh, R, Smith, E, Fathzadeh, M, Liu, W, Faramarzi,S, Subrahmanyan, L, Go, GW, McKenna, W and Mani, Rare nonconservative LRP6 mutations are associated with metabolic syndrome. Human Mutation, 2013 PMID: 23703864
- 13. (featured article) Singh R, De Aguiar RB, Naik S, Mani S, Ostadsharif K, Wencker D, Sotoudeh M, Malekzadeh R, Sherwin RS, Mani A. Lrp6 enhances glucose metabolism by promoting tcf7l2-dependent insulin receptor expression and igf receptor stabilization
- 12. Liu W, Singh R, Choi CS, Lee HY, Keramati AR, Samuel VT, Lifton RP, Shulman GI, Mani A. Low density lipoprotein (ldl) receptor-related protein 6 (lrp6) regulates body fat and glucose homeostasis by modulating nutrient sensing pathways and mitochondria
- 11. GO, GW, Mani A. Low-Density Lipoprotein Receptor (LDLR) Family Orchestrates Cholesterol Homeostasis. Yale J Biol Med. 2012 Mar ;85 (1):19-28 PMC3313535
- Ye ZJ, Go GW, Singh R, Liu W, Keramati AR, Mani A. Lrp6 protein regulates low density lipoprotein (ldl) receptor-mediated ldl uptake. J Biol Chem. 2012;287:1335-1344, PMC3256876
- 8. Keramati, AR, Singh, R, Lin, A, Faramarzi, S, Ye, Z, Mane, S, Tellides, G, Lifton, RP, and Mani, A. Wild-type LRP6 inhibits, whereas atherosclerosis-linked LRP6R611C increases PDGF-dependent vascular smooth muscle cell proliferation. Proc Natl Acad S
- 7. Keramati, AR, Anita Sadeghpour,A, M Farahani, M, Chandok, G and Mani, A. The non-syndromic familial thoracic aortic aneurysms and dissections maps to 15q21 locus. BMC Medical Genetics 2010, 11:143 PMC2958900
- Mutation in EGFP Domain of LDL Receptor-Related Protein 6 Impairs Cellular LDL Clearance. Wenzhong Liu, Sheida Mani, Nicole R. Davis, Nizal Sarrafzadegan, Paula B. Kavathas, Arya Mani. Circulation Research. 2008103:1280-8.
- Friedman T, Mani A, Elefteriades JA. Bicuspid aortic valve: clinical approach and scientific review of a common clinical entity.Expert Rev Cardiovasc Ther. 2008 Feb6(2):235-48.
- Mani A(Corresponding Author), Radhakrishnan J, Wang H, Mani A, Mani MA, Nelson-Williams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP. LRP6 mutation in a family with early coronary disease and metabolic risk factors.Science. 2007 Mar 2315(5816):1278-8
- Mani A, Radhakrishnan J, Farhi A, Carew KS, Warnes CA, Nelson-Williams C, Day RW, Pober B, State MW, Lifton RP. Syndromic patent ductus arteriosus: evidence for haploinsufficient TFAP2B mutations and identification of a linked sleep disorder. Proc Natl Ac