Influenza remains a serious public health concern, with approximately 1 billion people infected and hundreds of thousands of deaths every year worldwide. The development of a vaccine with universal protection, i.e. with the ability to protect all individuals, is still elusive. Part of the reason why current available vaccines still fail to promote such coverage is their incomplete activation of multiple immune system components that only together can completely protect individuals from influenza. More specifically, these vaccines, despite being efficient in the induction of antibody production, fail to generate cellular immunity induced by T cells, for example “helper” CD4+ T cells which are fundamental in the support of overall host immune protection. To successfully develop complete vaccines, we must improve our understanding about how these T cell responses form in response to natural infection. The purpose of this project, therefore, is to use research models and patient samples to determine how protective CD4+ T cell responses to influenza develop. Our research program has a long-standing interest in defining the mechanisms by which these memory cells form, especially inside the lungs, one of the primary sites of influenza infection. To investigate this topic, we use a myriad of cutting-edge quantification and imaging techniques, such as high-throughput spectral flow cytometry, primarily in mouse models. Our prior studies and preliminary data have revealed that extracellular ATP has a positive impact in the generation of protective lung CD4+ T cell responses against influenza. Extracellular ATP is a molecule that accumulates in the lungs following influenza infection as a “danger signal” – that is, a molecule that alerts the host immune system during situations of danger, typically an injury or infection. The main goal of this project is to determine the presence of lung CD4+ T cells responding to extracellular ATP in human lung samples from infected patients. Defining the validity of our mouse findings in patient samples will provide a clear translational potential for future therapeutic strategies our laboratory aims to do, with the final objective of improving the efficacy of influenza vaccines and achieve universal protection.

lschemic acute kidney injury is injury resulting from low blood flow to your kidneys. This type of kidney injury is the most common type of acute kidney injury and can happen following dehydration, bleeding, major surgery or other illness. Currently we do not have any treatments to prevent this type of kidney injury from happening. If the kidneys do not recover, dialysis or a kidney transplant remain the only options. The lack of treatment options for acute kidney injury highlights the need to better understand what causes injury to the kidneys when blood flow is reduced.

While it has long been thought that a lack of oxygen may be the main cause of kidney injury when blood flow to the kidneys is reduced, our recent work suggests that this might not be the case. Rather, when blood flow returns to the kidney after a period of low blood flow, red blood cells get trapped in the medulla or middle part of the kidney. As these red blood cells accumulate, they begin to break down, releasing toxic substances normally stored safely within the red blood cells themselves into the surrounding kidney tissue. This causes nearby tissues to die and kidney injury.

The data we have so far that supports this theory comes from animal studies. The goal of this proposal will be to test this hypothesis using kidneys obtained from humans that had acute kidney injury. In the first aim, we will look for signs that the kidney were not getting enough oxygen. We do not expect to find evidence of this. In the second aim we will look for signs that the kidneys were damaged by toxic materials released from red blood cells. In the third aim we will confirm that the injury that we do see happened to the kidneys because of the acute kidney injury and did not happen after death due to the natural breakdown of the tissue. By using computer models to analyze our data, our studies are designed to be able to identify the type of injury occurring in each kidney as well as where it occurs, without the bias that might come from humans scoring the samples.
These data will be the first to examine this hypothesis in human tissue and have the potential to change what we think causes acute kidney injury when blood flow is reduced. If correct, this would likely lead to new ways to treat acute kidney injury.

Hives, also known as urticaria, affect nearly one-quarter of individuals at some point during their lifetime. Although hives can be a sign of an allergy to a food or substance, some individuals experience hives in the absence of a clear cause over a period of several months to years. This condition is known as chronic spontaneous urticaria, which is abbreviated as CSU. Unfortunately, most people with this condition (CSU) continue to have symptoms even after taking antihistamines and these symptoms unfortunately have a major impact on their quality of life. Understanding the pathways that lead to CSU will aid in the development of new and more effective therapies for patients with this condition. We propose that skin mast cells play a key role in CSU. Mast cells release histamine and other products that contribute to the signs and symptoms of many allergic conditions including urticaria. Prior studies have shown that the majority of patients with CSU develop a raised lesion resembling a hive when their skin is injected with the serum component of their own blood. These results suggest the presence of factors in the serum of patients with CSU that are capable of activating their mast cells. One candidate pathway for mast cell activation in CSU is the MRGPRX2 receptor. MRGPRX2 receptors bind to both drugs and substances produced by other cells, triggering mast cells to release histamine and other inflammatory products. Studies have shown that patients with CSU have higher levels of cell products that activate MRGPRX2 in their blood. Compared to healthy individuals without hives, patients with CSU also have higher numbers of MRGPRX2 receptors in their skin. Injection of MRGPRX2-activating drugs into the skin has been shown to produce greater skin responses in patients with CSU compared to individuals without hives. While the exact role of MRGPRX2 in this condition is unknown, one study found that patients with chronic hives are more likely to have histories of reactions to drugs capable of activating MRGPRX2. Our proposal has three aims/components that will test the hypothesis that skin mast cells are activated in patients with CSU through the MRGPRX2 receptor. First, we will test serum from patients with CSU on skin samples obtained from skin reduction surgeries in combination with different inhibitors of mast cell activation. These inhibitors will allow us to determine the pathway through which mast cell activation occurs. Second, we will test skin from surgeries with specific cellular products, known as cytokines, to identify factors that affect MRGPRX2 receptor number and function in CSU. Finally, we will directly test skin from patients with CSU and individuals without hives to a compound that activates MRGPRX2 on mast cells. For each of these projects, we will measure histamine as a marker of mast cell activation. Successful completion of these aims will advance our understanding of the role of MRGPRX2 in CSU and will lay the groundwork for additional studies examining this pathway in patients with CSU.

Tendinopathy is a degenerative condition where tendons progressively weaken, causing persistent pain and sometimes leading to tendon rupture. To improve treatment and prevent tendon rupture, it’s important to understand what causes tendon degeneration in the first place. One major cause is overuse, which creates the accumulation of damage in the tendon. This damage not only weakens the tissue but also triggers a degenerative cellular response and the production of abnormal materials like cartilage, fat, and calcium deposits in the tendon. This degenerative cellular response weakens the tissue even more, worsening the condition. While it is unclear why tendon cells behave this way to overuse, scientists believe that this harmful cellular response happens because of how the cells sense tissue damage and the stretches applied to the tendon. However, most previous studies of how tendon cells response to stretch and other physical forces have looked at cells in an artificial environment that doesn’t fully replicate how tendons work in the body. To address this, we developed a model using mouse Achilles tendons to study the effect of overuse on cells while still in the tendon. Surprisingly, we found that tendon cells exhibited a degenerative behavior even though there was no evidence of a breakdown of collagen (a key protein in tendons). Additionally, the tendon cells only responded in a harmful way in low-oxygen conditions. The goal of this study is to figure out whether similar patterns happen in human tendons. That is, we will study whether collagen breakdown is absent in human tendinopathy, as it was in our mouse model, and whether there are low oxygen levels in the Achilles tendons of human tendinopathy patients. To do this, we will collect tissue from degenerated human Achilles tendons during surgery to treat tendinopathy and compare it with healthy donor tissue. Additionally, we will use an imaging device to measure the oxygen levels in healthy and tendinopathic Achilles tendons. Our hypothesis is that, like our mouse model, degenerated human Achilles tendons will not contain significant collagen breakdown but will have lower oxygen levels compared to healthy tendons. Our findings could lay the groundwork for future research to better understand how tendons degenerate, potentially leading to new, more effective treatments for tendinopathy that prevent tendon rupture.

By 2050, two in three adults in the United States are projected to suffer from obesity. Obesity is associated with an increase in life-threatening metabolic diseases such as type 2 diabetes and heart disease. Until recently, obesity had no cure beyond losing weight through diet and exercise. However, new medications known as GLP-1 agonists or incretin mimetics, like Ozempic or semaglutide, are revolutionizing how we treat obesity and related health problems. These drugs help people lose a significant amount of weight through simple weekly injections and have quickly become very popular with about 1 in 8 Americans reporting having tried them. Despite this success, we still don’t fully understand what these drugs do in specific organs of our body. This is essential to know as these drugs need to be taken for life to maintain the lost weight.

We study the effect of incretin mimetics on fat (or adipose) tissue. The adipose tissue expands during obesity to store excess nutrients. While this is a safe way of storing extra calories, over time, the adipose tissue can become unhealthy and contribute to metabolic disease. Within fat tissue are stem cells that help maintain and grow healthy fat. In obesity, these cells often stop working properly. Our new research in mice suggests that semaglutide not only leads to weight loss but also restores the ability of fat stem cells to function normally— possibly even better than when losing weight through diet alone. Now, we plan to study human fat tissue samples from patients taking semaglutide to see if the same improvements happen in people. Understanding these effects could help improve obesity treatments and lead to new therapies targeting fat tissue directly.

Chronic idiopathic constipation, or functional constipation, affects as many as 1 in 5 people and is a significant burden on the healthcare system. Severe, refractory constipation is associated with intestinal distention and often requires surgery to remove the distended, dysfunctional part of the intestine or divert the flow of stool. The enteric nervous system (ENS) is a key regulator of normal intestinal function. Disruption of the ENS results in a myriad of gastrointestinal disorders. Previous studies from our lab and others have found that chronic intestinal distention (i.e. over-stretching of the intestine due to constipation) results in alterations in the ENS and its surrounding extracellular matrix (ECM). Based on these preliminary findings, we hypothesize that chronic idiopathic constipation is caused by a vicious cycle of stretch-induced injury and fibrosis that ultimately leads to gut dysfunction and dysmotility. By comparing intestinal tissue specimens from patients with chronic constipation to normal age-matched controls, we seek to better characterize abnormalities in the ENS, ECM, and understand the cellular and molecular processes that lead to chronic idiopathic constipation.

This project aims to better understand the molecular mechanisms that drive this fibrosis in
chronic allergic asthma. We focus on two important regulatory pathways that act after genes are
transcribed: the MNK/eIF4E signaling pathway and the RNA-binding protein HuR. Both are
believed to influence how certain lung cells produce proteins that promote fibrosis, but their
specific roles in airway remodeling in asthma are not fully understood.

Our research explores how immune signals, particularly Th2 cytokines released by CD4+ T
cells, drive fibrotic transformation in lung mesenchymal cells (MCs), a cell population involved in
tissue repair and fibrosis. We hypothesize that these cytokines increase the phosphorylation of
a protein called eIF4E, changing how cells translate RNA into proteins like autotaxin and
collagen, which are key players in fibrosis. To investigate this, we will use a preclinical model of
chronic allergic airway inflammation triggered by house dust mite (HDM), a common asthma
allergen.

We are also requesting support from the Human Tissues and Organs for Research Resource
(HTORR) Pilot Award Program, administered by the National Disease Research Institute
(NDRI). This support will help us access lung tissue from asthmatic donors, a critical resource
we currently lack, to generate pilot data needed for our future NIH R01 grant application. Using
this tissue, we will isolate and cryopreserve lung MCs for current and future experiments. We
will also use precision-cut lung slices (PCLS) from asthmatic and control donors to evaluate
treatment responses in a more physiologic, multicellular setting.

As part of our study, we will test two promising drugs, eFT-508, which inhibits MNK1/2, and KH-
3, which blocks HuR. Both compounds are currently being explored for cancer treatment. We
aim to determine whether they can also reduce fibrosis and airway remodeling in asthma.
By combining human tissue studies and mouse models, this project seeks to uncover new
mechanisms that drive airway remodeling and identify novel targets for therapy. Our ultimate
goal is to develop more effective treatments for patients with allergic asthma who do not
respond well to current anti-inflammatory therapies.

More than 10% of US adults are diabetic, and an additional 40% are pre-diabetic. Obesity is the
leading risk factor for type 2 diabetes and defined as an expansion of fat tissue due to an
imbalance in caloric intake versus expenditure. How and where excess calories are stored
profoundly affects metabolic health: Metabolically healthy obese individuals have better visceral
fat tissue function compared to metabolically unhealthy obese individuals. This is due to an
improved ability of fat stem cells to generate enough new fat cells to store excess calories
properly. We do not yet know how excess calories activate fat stem cells and why this process
becomes impaired in some people, limiting our ability to target this pathway to prevent or cure
diabetes.

We showed that fat stem cells have an antenna-like structure called a primary cilium that
regulates the generation of new fat cells because it can sense and appropriately respond to
dietary, inflammatory, and hormone signals found in blood and fat tissue. We discovered that
primary cilia on many fat stem cells are lost in obese individuals and mice. We propose that fat
stem cells fail to become activated and generate new fat cells in sufficient numbers if the
primary cilium is either lost or “mistuned”.

Here, we request fat tissue samples from individuals with metabolically healthy obesity and
individuals with metabolically unhealthy obesity. We hypothesize that fat stem cells from
individuals with metabolically unhealthy obesity will have lost their ciliary antenna and be unable
to form new fat cells. In contrast, we hypothesize that fat stem cells from individuals with
metabolically healthy obesity will have a normal ciliary antenna and be able to readily make new
cells. We will complement the direct testing of our hypothesis with a panel of multi-omic
analyses to broadly survey changes in the fat tissue of individuals with metabolically healthy
versus unhealthy obesity. We envision that this broad survey will identify candidate drivers of
cilia loss in fat stem cells, which will form the foundation for a future R01 submission.

Scientists have learned a lot about how diabetes develops in younger adults, where the main problem is often “insulin resistance”—when the body no longer responds well to insulin. But in older people, the disease seems to be different. Many elderly individuals develop T2D without being overweight or having high cholesterol. Recent studies suggest that aging itself damages the beta cells in the pancreas, making them less able to produce insulin even if the rest of the body is working properly. Unfortunately, we still don’t know why aging harms beta cells, and we have no treatments designed to protect them in older adults.

One possible answer involves the tiny power plants inside each cell, called mitochondria. Mitochondria make energy, but over time they wear out and start to leak harmful molecules that damage the cell. Young cells have a way to clean up these damaged mitochondria through a process called mitophagy. But as we age, this system stops working as well, and worn-out mitochondria build up and contribute to cell failure. We believe this is happening in the beta cells of older adults, causing them to break down and stop making insulin.

Our project explores whether a natural compound called β-hydroxybutyrate (BHB) can help protect aging beta cells by restoring this clean-up system. BHB is a substance the body produces during fasting or when following a low-carbohydrate (ketogenic) diet. In other diseases related to aging, such as heart disease and Alzheimer’s disease, BHB has been shown to reduce inflammation, protect mitochondria, and improve cell survival. Our early studies in mice and human cells suggest that BHB may also protect beta cells by helping them remove damaged mitochondria. However, this has never been tested in pancreatic tissue from older adults.
We are requesting donated pancreatic tissue from recently deceased individuals through the HTORR program. By studying samples from middle-aged people, elderly people without diabetes, and elderly people with newly diagnosed diabetes, we hope to understand how aging changes beta cells and whether BHB can reverse those changes. If successful, this research could lead to a new way to treat or even prevent diabetes in older adults—using a safe, natural compound that the body already makes.

Our ultimate goal is to reduce the burden of diabetes in the aging population and help people live healthier, longer lives.

Diabetic kidney disease (DKD) is a serious complication of diabetes, impacting around one-third of individuals with the condition and increasing their risk of kidney failure and heart-related illnesses. One key factor in DKD is damage to the blood vessel lining in the kidneys, known as endothelial cell dysfunction (ECD). While it’s clear that ECD plays a role in DKD, the exact processes behind this dysfunction are not yet fully understood. Our research focuses on how DNA damage contributes to this dysfunction. We’ve identified a harmful molecule that forms due to metabolic changes in diabetes. This molecule damages DNA, disrupts repair processes, and alters gene activity, leading to increased inflammation and oxidative stress in kidney cells. We’ve also discovered that high blood sugar worsens the effects of this molecule, making DNA damage and cell dysfunction more severe. This project seeks to understand how these processes affect kidney blood vessels and contribute to DKD. By analyzing kidney samples from individuals with diabetes, we aim to uncover the links between DNA damage, blood vessel dysfunction, and DKD. These findings could pave the way for new treatments to prevent or slow the progression of kidney disease in people with diabetes.

Normally, the hear and leg muscles take in sugar (glucose) for energy using two types of transporters. In diabetes, one of these transporters (GLUT4), which depends on insulin, is less active. Surprisingly, we found that the other transporter, GLUT1, which works without insulin, becomes more active – likely due to the effects of KLF5. This leads to too much sugar entering the heart and leg muscles, which may not be used properly for energy and instead may be redirected into pathways that cause damage.

When we reduced KLF5 or GLUT1 activity in our experiments, we saw less stress and damage in the heart. These findings suggest that inhibiting this KLF5-GLUT1 pathway might help in preventing diabetes-related heart and leg muscle problems.

The goal of this pilot project is to better understand how this sugar-related damage happens in the leg muscles of people with diabetes. By confirming our mouse research in human tissue samples, we hope to pave the way for new treatments that can prevent leg muscle weakness and improve quality of life for people with diabetes.

Axial Spondyloarthritis and Acute Anterior Uveitis are autoimmune diseases of the spine and eye where the immune system attacks one’s own body. The target of this attack is not known. Our preliminary data suggest a new potential protein target. This proposal seeks to verify that our suspicion for this protein target is correct by using human joint and eye tissue to verify that the target is present in the affected organs. This may help will define why some individuals develop these disabling diseases.

More than 65% of the U.S. adult population is overweight, and more than 40% is obese. Obesity increases the risk for developing several serious diseases, including Type 2 diabetes, cardiovascular disease, and cancer, making it a major public health challenge. One of the factors that promotes the development of obesity is overeating, particularly for tasty foods that are generally high in fat, sugar, and total calories. The decision to seek out and eat these tasty, high calorie foods is controlled by a complex network of brain regions, and we now know that the function of this brain network is compromised in people with obesity in a manner that drives greater tasty food consumption, leading to more weight gain and worsening metabolic health. Importantly, we do not know how this brain network becomes dysregulated in people with obesity, and this information is needed to help improve obesity treatments. Prior research in rodents suggests that a specialized type of neuron called a “parvalbumin interneuron” is likely responsible for brain dysfunction during obesity, but this idea has not been tested in people. Thus, this pilot grant performs anatomical studies on donated postmortem brain tissue from people with comorbid obesity and type 2 diabetes (T2D) and compares the results to brain
tissue from demographically matched, normal weight, nondiabetic donors. We expect that the brains from people with obesity and Type 2 diabetes will show structural abnormalities in the parvalbumin interneurons that are consistent with altered brain function and elevated drive to eat tasty, high calorie foods. Ultimately, this information will indicate whether modulation of neural activity is a promising treatment approach for obesity and will help identify the specific brain locations with the greatest therapeutic potential.

The current medical model explains this problem through the hormone hepcidin. In CKD, hepcidin levels are elevated and suppress a protein channel called ferroportin, which normally allows iron to exit cells into the bloodstream. This “external lock” prevents iron from leaving storage cells such as liver cells (hepatocytes) and macrophages. This mechanism is well established and widely accepted.

However, growing evidence—including our preliminary data—shows that this model is incomplete. Even when ferroportin is present, iron export can remain impaired. This suggests that an additional, previously unrecognized mechanism exists inside the cell. We refer to this as an “internal lock.” Specifically, iron becomes trapped in a stored form bound to ferritin, while the small, usable fraction of iron—the labile iron pool (LIP)—is depleted. Without sufficient LIP, iron cannot be effectively exported, even if ferroportin is available.

Our experimental studies in mice demonstrate that this internal lock is not only present but functionally important. When ferritin regulation is disrupted in macrophages, iron export improves and anemia is alleviated—even though hepcidin levels remain high. These findings indicate that the external (hepcidin– ferroportin) mechanism alone does not fully explain iron trapping in CKD. Instead, both the external and internal locks together determine whether iron can be mobilized.

Despite this, what occurs inside human iron-storing cells remains unknown. Current knowledge treats each cell as a “black box”: it is known that iron accumulates, but how iron is partitioned within the cell—between stored and usable forms—has not been directly measured in human liver tissue.

This project will address this gap by analyzing donated human liver samples from individuals with and without CKD. Using advanced single-cell approaches, we will directly measure the balance between ferritin-bound iron and the labile iron pool within individual hepatocytes and macrophage subtypes. We will also assess key proteins involved in iron storage and export to determine how the internal lock operates in human disease.

By opening this cellular “black box,” this work will provide the first direct evidence of intracellular iron partitioning in the human liver in CKD. These findings will inform future strategies aimed not at simply increasing iron levels, but at restoring iron availability by targeting the mechanisms that trap iron inside cells.

Cardiovascular disease kills more American women than any other cause, accounting for one in five female deaths each year. The risk rises sharply at menopause, when ovarian hormone production permanently ends, and ultimately surpasses men’s risk. Approximately 1.3 million U.S. women enter menopause every year, yet the biological pathways that drive this surge in cardiovascular risk remain poorly understood, and no therapies specifically target the changes that occur in women’s bodies after this transition.

Our research investigates how fat-derived adipokines, specifically a recently discovered fat-tissue hormone called asprosin, impairs blood vessels in postmenopausal women. In a mouse model of postmenopause, we recently showed that these animals develop obesity and arterial stiffening, a loss of the normal flexibility that lets blood vessels expand and contract smoothly with each heartbeat, along with elevated asprosin levels in both blood and fat tissue. When we exposed isolated blood vessels to asprosin in the laboratory, they constricted abnormally, providing the first direct experimental evidence that fat-derived asprosin can impair blood vessel function. Mice, however, cannot fully replicate the human menopausal experience: their ovaries do not cease function the way human ovaries do, and they lack the abrupt shift in fat distribution and decades-long hormonal aftermath that define human menopause. Direct study of human tissue is therefore essential.

Working with donated tissue from NDRI, we are pursuing two goals. First, we want to find out which fat depot, the fat that surrounds the aorta, or the fat deeper in the abdomen, is responsible for producing excess asprosin after menopause, by comparing tissue from postmenopausal and premenopausal women. Second, using a cutting-edge imaging technology that maps gene activity inside individual cells, we are building the first detailed picture of how the postmenopausal artery wall breaks down, cell by cell. Our pilot data on two human aortic specimens (188,417 individual cells analyzed) already demonstrates the feasibility of this approach. The proposed imaging studies will be conducted using the CosMx platform available at the Biomedical Research, Innovation, and Imaging Center at the New York Institute of Technology.

Together, these results will show how fat tissue and the arterial wall interact to compromise vascular health after menopause and bring us closer to therapies that protect women’s hearts and blood vessels through a transition that nearly every woman experiences and that medicine has, until now, largely overlooked.

The data generated through this pilot study will provide the foundational human tissue evidence needed to support future R01 NIH grant applications extending this work into the mechanisms of postmenopausal vascular disease. None of this would be possible without the women and families who choose to make their tissue available for research; their gift is the foundation on which every finding in this work will rest.

Acute Respiratory Distress Syndrome (ARDS) is a severe manifestation of hypoxemic respiratory failure, leading to death in 30-40% of patients. Survivors frequently experience persistent physical, mental, and cognitive impairments, underscoring the substantial long-term healthcare burden of the disease. Despite its impact, no disease-specific treatments exist, reflecting a critical gap driven by our incomplete understanding of the mechanisms underlying ARDS pathophysiology. Hence, Dr. Rebecca Hough and her team aim to understand pathologic mechanisms of ARDS to advance the creation of new therapies.

The pathology that leads to ARDS occurs in alveoli where gas exchange takes place. Lung capillary leak causes pulmonary edema (fluid in the lungs) leading to low oxygen levels. Dr. Hough and her team made the surprising discovery that mitochondria in the endothelial cells which line the small blood vessels of the lung are crucial for the pulmonary edema formation that occurs in ARDS. They have used sophisticated genetic manipulation of mice, complemented by studies in endothelial cells in culture, to understand this mechanism. By examining the changes in mitochondrial metabolism that occur in the lung endothelium after pneumonia, they have identified a new, targetable mechanism of pulmonary edema in ARDS.

In this HTORR Pilot Award Program proposal, Dr. Hough and her team will translate their exciting findings in endothelial cells and in mice to human tissue samples. This is vital, as many animal studies do not translate into advances in clinical care. Dr. Hough’s proposal will compare endothelial mitochondrial responses in lungs from patients with and without ARDS. She will complement this work with experiments performed in human lung samples. In these experiments, she and her team will treat healthy lung samples with bacteria and assess the mitochondrial and metabolic impact of these treatments. This will allow Dr. Hough her team to perform mechanistic work on human samples.

Here, Dr. Hough and her team will evaluate the hypothesis that capillary mitochondria alter prostaglandin signaling in capillary endothelial cells, leading to pulmonary edema. They will use advanced imaging of human lung samples to understand these mechanisms, with an aim of moving the needle on the high mortality rate of ARDS. These proposed studies will provide essential preliminary data for an R01 application on metabolic mechanisms of ARDS.

Every day, our lungs are exposed to billions of tiny particles from the air we breathe, including dust, pollutants, and germs. To stay healthy, the lungs rely on a natural cleaning system that traps these particles in mucus and moves them out of the airways. In healthy lungs, this mucus is thin and easy to clear. However, in diseases where airways become blocked with mucus, it becomes thick, sticky, and difficult to remove, leading to breathing problems and infections. Current treatments do not effectively fix this underlying mucus problem.

Our research aims to better understand how the cells in the lungs produce and manage mucus. Some specialized cells are able to make and release very large amounts of mucus, but how they do this without damaging themselves is not well understood. We are particularly interested in a protein called MIA3, which helps move large molecules inside the cell, and in how certain structures within these cells are organized to handle the heavy workload of mucus production.

We believe that mucus-producing cells have unique features that allow them to safely produce and transport large amounts of mucus. Over the next two years, we will study how MIA3 helps move mucus inside cells and whether problems in this process contribute to the buildup of thick, harmful mucus in lung disease.

This work will help us better understand why mucus becomes abnormal in certain lung diseases and could point to new ways to treat these conditions. Ultimately, our goal is to find better strategies to restore the lung’s natural cleaning system and improve breathing and quality of life for patients.

Osteoarthritis (OA) is one of the most common and debilitating joint diseases in the world, affecting more than 32 million Americans and hundreds of millions of people globally. It causes progressive breakdown of the cartilage that cushions our joints, particularly the knee, leading to chronic pain, stiffness, and loss of mobility that severely impacts quality of life. Despite decades of research, there is still no medication available that can stop or reverse the underlying disease process. Current treatments, such as pain relievers and anti-inflammatory drugs, only manage symptoms and do not address the root biological causes of cartilage deterioration. Many patients ultimately require total knee replacement surgery, which carries significant risks, costs, and recovery burdens.

Our research team at the Center for Nanomedicine, Brigham and Women’s Hospital and Harvard Medical School, is developing a new approach to treat OA at its biological root. We have engineered tiny particles, thousands of times smaller than a human hair, called lipid nanoparticles (LNPs), which are designed to carry a genetic medicine called messenger RNA (mRNA) directly into cartilage cells known as chondrocytes. The mRNA instructs these cells to produce a natural protein called Klotho, which is known as a powerful “longevity factor” that protects cells from aging and deterioration. In addition, our nanoparticles are loaded with NAD+, a naturally occurring molecule that boosts cellular energy and resilience. Together, this dual-action approach targets two of the key biological mechanisms driving OA, cellular aging and metabolic dysfunction, with the goal of restoring cartilage health from within.

Our laboratory studies in mice have already shown very promising results. Our nanoparticles successfully penetrate deep into mouse cartilage tissue, both in healthy joints and in joints with OA, and effectively deliver their therapeutic cargo to chondrocytes. However, human cartilage is fundamentally different from mouse cartilage. It is significantly thicker, denser, and more structurally complex, meaning that results in animals do not automatically predict what will happen in human tissue. Before we can responsibly move this therapy toward clinical testing in patients, we must first demonstrate that our nanoparticles can penetrate and function effectively in actual human cartilage tissue.

This is precisely what this pilot study aims to achieve. Through the NDRI-HTORR Pilot Award, we will obtain human knee cartilage tissue specimens from two groups of donors of young healthy individuals and older donors with confirmed OA. Using these human tissue samples in controlled laboratory experiments, we will directly test whether our nanoparticles can penetrate human cartilage, reach chondrocytes, and successfully deliver their therapeutic mRNA cargo. Comparing results between healthy and OA cartilage will also help us understand how the structural changes that occur in diseased joints affect nanoparticle delivery, critical information for optimizing our therapy for real-world patients. The data generated through this pilot study will provide the foundational human tissue evidence needed to support applications for larger NIH grants, ultimately accelerating the development of a first-of-its-kind disease-modifying nanomedicine therapy for the millions of patients living with osteoarthritis worldwide.

The proposed study aims to bridge this knowledge gap by studying the cell composition, cell activation states, and CCC in human DRG. The proposed research will definitely provide foundational knowledge of the sensory neuron microenvironment, including cell types/subtypes, their spatial organization, and gene expression in physiological conditions. It will also develop protocol and analytic pipeline to decipher CCC in human DRG from CPP donors.