Scientific Track
The CRN 2025 Scientific Track will focus on supporting high-priority, mechanism-focused projects to drive new ideas into the Parkinson’s disease (PD) R&D pipeline.
Areas of Focus
CRN 2025 calls for the scientific track are centered around dissecting the mechanisms that can contribute to PD heterogeneity, with a specific focus on the following areas.
Age is a well-established risk factor for PD; however, it is still unclear how aging-influenced processes contribute to the underlying pathogenesis of PD. This call would support discovery efforts to understand pathogenesis and progression of PD in the context of biological aging, exploring whether targets for aging-influenced processes are involved in changing the timing of onset and rate of progression of PD. For this call, a variety of well-validated models can be utilized from in vitro, in vivo, in silico, and human cohorts.
In scope:
The types of applications we seek to fund would focus on the following areas of study:
- Investigating whether factors known to rejuvenate the aging brain can influence PD disease onset and rate of progression
- Exploring compensatory biological mechanisms associated with aging and their impact on PD disease progression
- Studying interactions between PD risk genes and age in PD onset and progression to understand what characteristics are associated with slow vs. fast progression in PD
Out of scope:
- Active cohort recruitment (however existing aging cohorts and data already collected can and should be leveraged)
Human post-mortem data has demonstrated that co-pathology exists between PD, Lewy Body Dementia, and Alzheimer’s disease. This call aims to better understand the mechanisms that impact the drivers and downstream effects of co-pathologies in the context of PD development and progression. Although the primary focus is on neurodegenerative co-pathologies, exploration into known co-occurring conditions, such as Inflammatory Bowel Disease, can also be considered.
In scope:
The types of applications we seek to fund would focus on the following areas of study:
- Human pathology studies or other models that can help us understand the temporal and spatial sequence of co-pathology in the brain across different neurological diseases under physiologically relevant conditions (e.g., how do physiologically relevant levels of tau, amyloid beta, tdp43, and alpha-synuclein interact and influence disease processes)
- Examining the role of different brain cell types contributing to or being impacted by various protein aggregates associated with neurodegenerative diseases
Out of scope:
- Studying the phenomenology in patient populations to examine the temporal onset of protein aggregate pathologies
- Projects primarily focused on diseases other than PD or projects that do not have a direct link to PD
A number of environmental factors including pesticides, industrial chemicals, and other toxins have been linked to an increased risk of developing PD. A greater understanding of the mechanisms through which these various environmental triggers, either in isolation and in combination, impact PD risk and/or progression and the converging/diverging interactions of these mechanisms with known genetic, age-related, biological sex-related, and other pathogenic pathways will be prioritized. This theme would seek to understand how various suspected environmental triggers influence processes implicated in PD and/or novel pathways not previously linked in PD.
In scope:
The types of applications we seek to fund would focus on the following areas of study:
- Identifying converging mechanisms of suspected external environmental risk factors (e.g., viruses, toxins, pesticides) on PD development and/or progression including examination of gene-environment interactions
- Identifying pathways that are protective from the neurotoxic effects of environmental on PD triggers
- Understanding how biological sex differences and/or age-related differences contribute to these converging mechanisms/pathways proposed
Out of scope:
- Broad fishing expeditions exploring the PD exposome in prospective studies
- Identification of new environmental risk factors in large epidemiological cohorts
- Survey questionnaires are out of scope
- Studies focused exclusively or in large part on the gut microbiome
PD is largely identified based on the hallmark motor clinical symptoms of rigidity, bradykinesia, and tremor, but clinical presentation varies widely, and non-motor symptoms can be equally or more debilitating to patients. Better efforts in modeling the various motor and non-motor symptoms that recapitulate the key temporal aspects of disease progression will be critical to identifying the mechanisms and circuits that play a role in the development of these symptoms. Modulation of these circuits and pathways using novel tools and technologies could then be tested as potential treatment strategies for people with PD. We will prioritize applications that can connect preclinical and clinical dataset findings to better explore and understand how heterogeneity in PD circuit biology manifests as symptomatic heterogeneity.
In scope:
The types of applications we seek to fund would focus on the following areas of study:
- Manipulation of circuits to understand the mechanisms underlying functional changes to circuits contributing to PD non-motor behaviors. For these projects, preference will be given to those studies that prioritize the unmet needs of the PD patient community (e.g., sleep, pain, cognition dysfunction, etc.)
- Development of new tools to query the circuit will not be prioritized. Rather we encourage individuals to apply the existing toolkits to glean insights into PD circuit pathology. However, if strong justification is made for why such a tool is needed to answer the question, we will consider it.
Out of scope:
- Studies that do not have a direct link to human PD datasets
- Human studies that cannot be completed in three years
- Circuits that only focus on well studied motor symptoms
Considerable evidence supports the hypothesis that alpha-synuclein aggregates may initiate organelle damage and precipitate events that lead to dopaminergic cell death. Although considerable progress has been made in identifying various clearance pathways that could potentially play a role in PD pathogenesis, more discovery efforts are essential to elucidate the key processes of aggregate turnover, spread, or removal through autophagy, glymphatic clearance, and other mechanisms with an eventual goal of identifying druggable biological targets for subsequent efforts. ASAP will prioritize applications that address the role of these mechanisms in mediating Lewy body pathology and selective vulnerability of dopaminergic neuron populations.
In scope:
The types of applications we seek to fund would focus on the following areas of study:
- Studying the pathways of aggregate turnover on the molecular or systems level, with a focus on specific targets (should not be a discovery expedition to identify new targets)
- Studying the role of sleep abnormalities in impacting glymphatic system
Out of scope:
- Studying pathways that cannot be directly linked to PD biology
- Identifying new autophagy genes through screening assays
The introduction of the alpha-synuclein seed amplification assay (alpha-syn SAA) has revolutionized how we think about biological staging of neuronal alpha-synuclein disease for PD. However, the exact alpha-synuclein species detected by the assay, whether there is an additional co-factor required to initiate seeding, and the assay’s relevance to PD is largely unknown. This theme calls for conducting a comprehensive biochemical and biophysical assessment of human brain tissues and other biomaterials to understand what that seeding agent is.
In scope:
The types of applications we seek to fund would focus on the following areas of study:
- Biochemical and biophysical analysis within human brain, CSF, and other biomaterials to identify the seeding factor for the alpha-synuclein SAA assay and understanding the biodistribution of this factor across different biomaterials (e.g., CSF vs. blood vs. brain regions). Based on those findings, early assay development to optimize and improve current alpha-synuclein seed amplification assays can be part of the proposal.
- Mapping of the post-translational modifications of alpha-synuclein across different biomaterials to understand how different alpha-synuclein post translational modifications:
- Associated with clinical symptoms (e.g., motor vs. non motor symptoms in PD)
- Compare across the PD clinical spectrum (e.g., multiple system atrophy, Dementia with Lewy Bodies, Lewy Body Dementia)
Out of scope:
- Studying alpha-synuclein post translational modifications in animal model systems (this is a human focused call)
- Understanding the endogenous function of alpha-synuclein
Requirements
Projects
Projects supported within the scientific track must have a tie to human biology.
Team Composition
Core leadership of each team must have the following:
- PI Count: 3-5 Principal Investigators all with PhD, MD, or equivalent degrees
- Appointed Lead: Coordinating Lead Principal Investigator with an academic appointment and be in an independent faculty position or equivalent
- Early Career Investigator: At least 1 Early Career Investigator (ECI) in the position of Co-Investigator
- Multidisciplinary: At least 2 different disciplines represented
- Multi-institutional: 2 (min) – 5 (max) participating institutions represented
- Time Commitment: All Core Leadership members are expected to allocate a minimum of 25% time and effort to the research project
Open Science Policy
ASAP is built on strong open science policies. Awardees and team members agree to follow all ASAP open science policies.
Call Details
- ASAP will open the call for Letters of Intent (LOIs) in January 2025
- LOI submissions will be due in March 2025
- ASAP will announce funding decisions in November 2025
- Awarded teams will receive funding of up to $3M per year for three years
CRN 2025 Funding Updates
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