2008 |
Behrouz, Bahareh |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Parkin and Differential Susceptibility of Dopamine Neurons in Parkinson's Disease @ Michigan State University
[unreadable] DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a debilitating neurodegenerative disorder that causes severe motor impairments. Progressive degeneration of nigrostriatal dopamine neurons underlies these motor symptoms and there is currently no way to stop or slow this neuronal loss. Abnormal dopamine metabolism has been proposed to underlie the degeneration of these neurons. However, all dopamine neurons are not affected to the same extent in PD. In fact, while there is severe loss of midbrain nigrostriatal dopamine neurons, the hypothalamic tuberoinfundibular dopamine neurons remain intact. Our preliminary data demonstrates that a similar pattern of susceptibility in these dopamine neuronal populations when they are exposed to complex I inhibition in a mouse model of PD. Furthermore, we have ruled out several extrinsic factors previously hypothesized to underlie this differential susceptibility. We have also demonstrated that the nigrostriatal and tuberoinfundibular dopamine neurons have a similar initial response to complex I inhibition but that only tuberoinfundibular dopamine neurons are able to recover. The timeline of this recovery has been characterized and is very rapid. Our preliminary data also suggests that the protein parkin may be involved in this differential susceptibility. Constitutive parkin mRNA levels are higher in the cell body regions of tuberoinfundibular dopamine neurons when compared to cell body regions of nigrostriatal dopamine neurons. Furthermore, at the critical time point when tuberoinfundibular neurons show recovery in response to complex I inhibition, parkin mRNA levels also dramatically increase. Parkin is an E3 ligase that tags misfolded and abnormal proteins for degradation and plays a protective role in several models of neurotoxicity including mitochondrial dysfunction, oxidative damage, synuclein toxicity and proteasome inhibition. The proposed experiments will determine whether higher levels of parkin in the tuberoinfundibular dopamine neurons protect them from complex I inhibition. This will be determined by decreasing the expression of parkin mRNA and protein in tuberoinfundibular dopamine neurons and determining whether they become susceptible to complex I inhibition. Furthermore, the proposed studies will determine whether increasing parkin expression in the nigrostriatal dopamine neurons will protect them from complex I inhibitor toxicity. The proposed experiments will enhance our understanding of differential susceptibility of dopaminergic neurons in response to complex I inhibition. The results may be further translated into neuroprotective strategies that can prevent the ongoing degeneration of dopamine neurons in PD. [unreadable] [unreadable]
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1 |
2020 |
Behrouz, Bahareh |
R43Activity Code Description: To support projects, limited in time and amount, to establish the technical merit and feasibility of R&D ideas which may ultimately lead to a commercial product(s) or service(s). |
Discovery and Development of Usp30 Inhibitors as Disease-Modifying Therapy For Parkinson's Disease. @ Vincere Biosciences, Inc.
PROJECT SUMMARY/ABSTRACT The proposed Phase I research is designed to establish the technical/scientific merit and feasibility of developing first/best-in-class, USP30 inhibitors for the treatment of Parkinson?s disease (PD), an age- associated neurodegenerative disorder second only to Alzheimer?s disease (AD) in prevalence. No therapy that can slow or stop the progression of PD currently exists. Instead, treatments for PD, which affects 10 million people worldwide, merely augment dopaminergic neurotransmission to provide symptomatic benefit. To address this unmet need, Vincere Biosciences has initiated a platform to develop small molecules targeting the parkin-USP30 ubiquitination pathway, which represents a key regulator of mitochondrial homeostasis, as a means of slowing disease progression. Converging lines of evidence ? human pharmacology, genetics, tissue pathology and animal model studies ? indicate that deficits in mitochondrial quality control pathways underlie PD pathogenes. While parkin, an E3 ubiquitin ligase, drives mitophagy by adding ubiquitin chains to proteins on damaged mitochondria, USP30 removes these chains to inhibit clearance of the damaged mitochondria, thus acting as the yin to parkin?s yang. Of note, functional genomic studies in mammalian cells and flies have validated USP30 as a key target of mitochondrial quality control. While mitochondrial abnormalities have long been implicated in sporadic PD, compelling scientific rationale also now exists for restoring mitochondrial health in AD. By inhibiting USP30, we aim to indirectly enhance parkin?s downstream signaling, thereby increasing mitophagy and restoring mitochondrial homeostasis. In so doing, we will test the hypothesis that USP30 inhibitors promote the clearance of damaged mitochondria, thereby attenuating the pathogenic cascade associated with PD pathogenesis. We have identified several hit compounds that potently inhibit USP30 activity in vitro, and demonstrate cellular activity without cytotoxicity in human primary fibroblast cells. Moreover, our exciting preliminary data indicate that we have rigorous flow scheme assays and starting chemical scaffolds in place to deliver: two distinct lead series with IP potential for lead optimization (Aim 1); and, up to 12 optimized compounds for further in vivo pharmacokinetic (PK) and target modulation/efficacy assessment and preclinical development (Aim 2). In the proposed Phase I studies, we will answer the following technical questions: 1) Can we identify potent and patentable USP30 inhibitors with sufficient selectivity; that, 2) Induce mitophagy in human cells without cytotoxicity and effects of basal mitochondrial membrane potential; and, 3) Display desired in vitro ADME properties engineered to enable in vivo proof of concept studies and preclinical development in Phase II? A future Phase II will carry these molecules through in vivo PK, PK-Pharmacodynamic (PK-PD) research, and preclinical development (Investigational New Drug (IND)-enabling studies) to position our molecules, for out-license or partnership with big pharma/biotech, who have already expressed interest in our program.
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0.913 |