Current Projects
Of major interest in the lab is the question how stem cells survive and function in an aging brain environment. Neural stem progenitor cells (NSPCs) persist throughout life in the adult rodent brain, generating young neurons for the olfactory bulb (OB) and hippocampus that form an integral part of the normal functional circuitry. NSPCs mainly inhabit two distinct and specialized niches: (a) the SVZ, lining the lateral ventricles in the forebrain, which contains the larger pool of stem cells; and (b) the SGZ in the dentate gyrus (DG) of the hippocampus. While such active NSPCs exist, their regenerative ability is affected with advancing age. Our studies have identified a specific temporal pattern of change in NSPC dynamics, which highlights a critical time during middle-age (13–15 months) when NSPC activity strikingly declines. These studies also discovered the reduced expression of the NRF2 transcription factor as an important mechanism mediating this phenomenon. From a basic science perspective, the discovery of Nrf2’s role provides a robust framework for understanding fundamental aspects of NSC biology and ageing. From a clinical perspective, this finding has important implications for improving NSC function with age and developing targeted therapeutics for age-related neurological disorders. We are currently pursuing studies which address the molecular mechanisms governing Nrf2 function in the NSCs, and how it is affected by age and sex-differences.
Stem Cells and Aging
Stem cells have the unique ability to induce plasticity and repair in the nervous system. On one hand, they can give rise into mature neuronal and glial cell types, and act as a source of new cells. On the other hand, stem cells have a natural ability to promote cell survival, regeneration, and homeostasis in the brain. Our research broadly focuses on understanding the scope and dynamics of such stem cell effects, which can restore and revitalize the neural environment. In particular we are interested in using the information gained from these studies to develop rational approaches to tackle age-related neurodegenerative diseases such as Parkinson's disease (PD). We mainly utilize rodent and human cellular systems to address these questions.
Human patient-derived cells for modeling PD, biomarker discovery, and testing precision treatments
A crucial factor limiting scientific progress in understanding Parkinson’s disease (PD) pathogenesis has been the lack of robust research models, particularly in the form of relevant neural tissue from PD patient populations. In this context, our lab has created human induced pluripotent stem cell (iPSC) lines reprogramed from skin fibroblasts of sporadic PD patients. These skin fibroblasts and iPSCs are currently being used in the lab as powerful patient-specific systems to generate disease relevant neural cell-types and investigate mechanisms contributing to PD. We are also developing biomarker and drug screening platforms, using human fibroblasts and iPS-derived cells, relevant to PD. In other work, we have also developed an iPSC-based model to study mechanisms underlying childhood epilepsy (collaboration with the Michael Hammer Lab).
Drug discovery and Therapeutics
Despite its debilitating nature, characterized by motor deficits and neurocognitive decline, PD has no cure. The current care for PD is symptomatic, with no existing therapy capable of altering the course of the disease. While this symptomatic treatment can provide transient relief during early stages of the disease, the side effects of treatment begin to outweigh the benefits over time. Therefore, therapeutics that can intervene in the progression of PD are crucially needed. From this perspective, we are investigating promising drug candidates in our rodent and human models of PD. Current endeavors focus on testing agents targeted at improving mitochondrial function (collaboration with the Rick Schnellmann Lab), and novel glycosylated peptides to reduce oxidative stress, inflammation and the aggregation of pathological proteins such as alpha-synuclein (collaboration with the Torsen Falk and Robin Polt Labs). Additionally, we are also involved in drug discovery studies to address cognitive defects in Alzheimer’s disease (Gregory Thatcher lab).
Peptides with neuroprotective potential have increased safety profiles because their metabolites are simple amino acids. However, they are rapidly degraded and have difficulty crossing the blood brain barrier. Glycosylation of peptides overcomes these challenges by increasing stability and enhancing blood brain barrier penetration, thus increasing their clinical applicability. Two such peptides we are testing in PD models are glycosylated PACAP and Ang1-7 (PNA5).
