Kumar, J. M. | bioRxiv Science

bioRxiv2022

A Novel congenic Mouse Model to study Obesity, Diabetes and NAFLD

The genetic background of the mutant mouse strain plays an important role in disease development. We investigated whether Lepr mutation on different genetic background (WSB/EiJ) influences the development of obesity, diabetes and non-alcoholic fatty liver diseases (NAFLD). For this study heterozygote (db/+) mice were backcrossed with WSB/EiJ strain (that is resistant to obesity and NAFLD) for more than 10 generations and intercrossed for five generations having Lepr mutated gene incorporated in WSB/EiJ background. The newly derived congenic strain was assessed and related with the B6.db strain and WSB/EiJ strain for the development of obesity, NAFLD. The Lepr mutated congenic strain on the WSB/EiJ background gained significant body weight and showed other characteristic features of obesity. However, the incidence of diabetes, NAFLD, and other kidney complications were not observed in this strain. The novel congenic mouse strain having Lepr gene on WSB/EiJ background would be a promising model for the study of obesity without NAFLD and will also help to understand the various mechanisms involved in the development of NAFLD.

physiology↗

bioRxiv2016

Delivery of BACE1 siRNA mediated by TARBP-BTP fusion protein reduces β-amyloid deposits in a transgenic mouse model of Alzheimers disease

Systemic delivery of nucleic acids to the central nervous system (CNS) is a major challenge for the development of RNA interference-based therapeutics due to absence of stability, target specificity, non-permeability to the blood-brain barrier (BBB), and mainly due to lack of suitable carriers. Using a designed bi-functional fusion protein TARBP-BTP, very recently we demonstrated knockdown of target genes in the brain of both A{beta}PP-PS1 (Alzheimers disease, AD) and wildtype C57BL/6 mice upon systemic delivery of a single dose of siRNA. In this report, we further substantiate this hypothesis through an extended study in A{beta}PP-PS1 mice, which upon treatment with seven doses of {beta}-secretase APP cleaving Enzyme 1 (BACE1) siRNA, led to target-specific effects in the mouse brain. Concomitant gene silencing and consequent reduction in plaque load in the cerebral cortex and hippocampus (>60%) in mice treated with TARBP-BTP:siRNA complex further led to improvement in spatial learning and memory, which was assessed and verified through Morris Water Maze test that revealed significant improvement in cognitive function. Moreover, the treatment did not induce any adverse effects as revealed by the histopathology of different organs. The work validates the efficiency of TARBP-BTP fusion protein as an efficient mediator of RNAi giving considerable scope for future intervention of neurodegenerative disorders of the CNS through the use of short nucleic acids as gene specific inhibitors.

neuroscience↗