Age-Related Disorders and Infectious Disease lab
Our long term research interests involve understanding key regulatory pathways and how alterations in gene expression contribute to human aging, age related disorders and infectious diseases. To achieve this, we identify new innovative genetic targets which might play a role in diseases and disorders. Thereafter, we study the physiological role of the target genes with the ultimate goal to design synthetic or natural drugs to modulate these targets/pathways.
The lab utilizes novel molecular and cell biology tools and techniques, biochemistry, in vitro model systems, MEFs, mice genetics, microbiology and CRISPR/Cas9 based functional genomics screening approaches.
We are currently focusing on the following projects:
Role of Reduced protein translation in neurodegenerative disorder
Proteostasis is essential for optimal cell growth and survival, dysregulation of which causes protein aggregation and is associated with age-related neurodegenerative diseases such as Parkinson’s disease (PD). mTOR, a master regulator of proteostasis, is dysregulated in many diseases, such as PD. A key downstream substrate of the mTORC1 complex, eukaryotic translation initiation factor 4E binding protein (4EBP1), has been linked to enhanced longevity in invertebrates. Active 4EBP1, by sequestering eIF4E from eIF4G, blocks 5’ Cap dependent mRNA translation. As reduced protein synthesis may decrease stress on cellular protein quality control systems in the cell, the overall goal of this project is to examine the role of reduced protein translation in neuroprotection, by testing if increased expression of 4EBP1 can ameliorate toxicity in a series of in vitro and in vivo models of PD.
The outcome from this project will not only confirm the importance of reduced protein translation in neuroprotection, but, if successful, will also seek to establish the mechanistic pathways underlying neuroprotection promoted by reduced protein translation. This work will thus have therapeutic potential for debilitating neurodegenerative disorders and possibly other mitochondrial diseases.
To identify activators and repressors of eukaryotic Initiation Factor 4E Binding Protein as potential therapeutic targets
Aberrant mTOR phosphorylation and its downstream effectors has been implicated in many malignancies such as neuroblastoma, glioblastoma multiforme, astrocytoma among many other forms of cancer; age related neurodegenerative disorders such as Parkinson’s Disease; and neurodevelopment disorders such as autism spectrum disorders. So a clear understanding of the downstream effectors of the mTOR pathway is quintessential to explore avenues to improve health as we age and combat age related disorders. We are focusing on 4E-BPs which are downstream effectors of mTOR pathway. The overarching goal of this project is the biological characterization of the 4E-BPs with a focus on identifying their upstream activators or repressors which may represent drugable targets for treatment in cancer of the CNS and neuroinflammatory disorders. This work will thus have therapeutic implications for developing treatments for PD and possibly other pathologically similar neuroinflammatory disorders.
Role of mini-chaperones in alleviating the molecular pathophysiology of Amyotrophic Lateral Sclerosis
Accumulation of misfolded protein aggregates in the CNS is a common feature of many neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS). A unifying mechanism of neurodegeneration in these diseases is unregulated protein aggregation & impaired protein clearance via the autophagy-lysosomal pathway (ALP) which results in disruption of protein homeostasis. This unwanted toxic proteins aggregation leads to disruption of normal cellular functions, oxidative stress, nucleo-cytoplasmic transport defect, disruption in RNA processing, protein translation, mitochondrial dysfunction, nucleolar stress and ultimately neuronal death. ALS is a neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord. Small molecules, peptides, molecular chaperones and antisense oligos are currently being pursued worldwide to address the issues that arise due to protein misfolding and aggregation. We have obtained a patentable, cell-penetrable caspase-3 activable, protease resistant mini-chaperones which have anti apoptotic effects in in vitro models of cytotoxicity and in AD. We propose to use established in vitro C9ORF72 hexanucleotide repeat associated dipeptide neuronal toxicity models of ALS to check the efficiency of the mini chaperones in reducing neuronal toxicity as an effective therapeutic molecule for ALS. This project we are pursuing in collaboration with Dr. Dinesh Upadhya.