RFA-TS-24-010: Ambient Air Pollution as a Potential Risk Factor for ALS - Using a Multiomics Approach in a High-Quality Epidemiologic Study

Karolinska Institute, Stockholm

Investigators

Abstract

Project summary Air pollution is gaining momentum as an important contributor to ill health and has recently started to be studied as a potential risk factor for amyotrophic lateral sclerosis (ALS). The currently existing literature is, however, limited by methodological limitations, and the underlying mechanisms linking together air pollution and the initiation and progression of ALS are still largely unknown. With the ultimate goal of providing important new knowledge for disease prevention among high-risk individuals and identifying novel therapeutic targets, the overarching aim of this research project is to use the extensive data and biospecimens collected in a unique Swedish national ALS registry to identify and evaluate air pollution, alone or together with another proposed risk factor for ALS, namely infections, as a potential risk and prognostic factor for ALS, focusing on understanding alterations in the expression of proteins related to oxidative stress and inflammation, the immune responses, and the gut microbiome as potential underlying mechanisms. In the specific Aim I, we will assess the role of air pollution, alone or together with infection, on the risk and prognosis of ALS, using prospectively and independently collected data from the Swedish national health registers (including the Motor Neuron Disease [MND] Registry). We will contrast ALS patients of different clinical phenotypes with two control groups: disease-free full siblings and age- and sex-matched population controls. In the specific Aim II, we will characterize the role of air pollution, alone or together with infection, on 1) the expression of proteins related to oxidative stress and inflammation in blood and cerebrospinal fluid (CSF) and 2) the composition and functionality of the gut microbiome in ALS patients, compared to controls, using the ALSrisc Study. In the specific Aim III, we will use single-cell RNA sequencing to profile the immune cells of blood and CSF to understand the role of air pollution, alone or together with infection, on immune responses in ALS. In summary, this proposal addresses both of the two objectives listed by NOFO RFA-TS-24-010, namely 1) Identify potential risk factors for ALS in humans and 2) Characterize how or why the(se) risk factors are potentially associated with or contribute to the etiology, progression, and pathophysiology of ALS in humans. Findings from this project are expected to advance our understanding of ALS as a disease and provide new knowledge for disease prevention and treatment, fully supporting the ATSDR National ALS Registry's mission. The findings will also help ATSDR better prioritize topics for future research initiatives and inform the development of new ATSDR National ALS Registry risk factor surveys for persons with ALS. Finally, the proposed program of research also addresses the Healthy People 2030 priority area of environmental health infrastructure and surveillance and is in alignment with CDC/ATSDR’s performance goal to conduct a targeted program of research to identify, characterize, and monitor health outcomes and environmental exposures to guide actions that protect and promote health. Specifically, our research supports the Healthy People 2030 goal to promote healthier environments and Healthy People Objective EH-06 to reduce the amount of toxic pollutants released into the environment. The research proposal intends to fall under Funding Option B: to support novel ALS risk factor research investigations that may or may not have an existing evidence base, maybe supported by limited and insufficient preliminary research, and are exploratory and developmental in nature.